CN108368147A - Nucleotides for the treatment of cancer - Google Patents

Nucleotides for the treatment of cancer Download PDF

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CN108368147A
CN108368147A CN 201680041222 CN201680041222A CN108368147A CN 108368147 A CN108368147 A CN 108368147A CN 201680041222 CN201680041222 CN 201680041222 CN 201680041222 A CN201680041222 A CN 201680041222A CN 108368147 A CN108368147 A CN 108368147A
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cancer
compound
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leukemia
alkyl
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CN 201680041222
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C·B·道森
D·杜汉
J-L·帕帕林
C·C·帕西
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南方研究院
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07HSUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06Pyrimidine radicals
    • C07H19/10Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
    • C07H19/11Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids containing cyclic phosphate
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • A61P35/02Antineoplastic agents specific for leukemia
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07HSUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06Pyrimidine radicals
    • C07H19/10Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K2121/00Preparations for use in therapy

Abstract

本申请涉及新颖的如权利要求1中所要求的式(I)核苷衍生物、包含所述化合物的药物组合物、其制备方法和使用其治疗癌症的方法。 The present application relates to novel formula (I) in a nucleoside derivative as claimed in claim, pharmaceutical compositions comprising said compounds, their preparation and method of use thereof in the treatment of cancer.

Description

用于治疗癌症的核苷酸 Nucleotides for the treatment of cancer

技术领域 FIELD

[0001] 本文提供了核苷衍生物、包含所述化合物的药物组合物、其制备方法和使用其治疗癌症的方法。 [0001] Provided herein nucleoside derivatives, pharmaceutical compositions comprising said compounds, their preparation and method of use thereof in the treatment of cancer.

[0002] 在某些实施方案中,提供了核苷和核苷酸化合物和前药,其显示治疗例如人类肝癌的显著功效和生物利用率。 [0002] In certain embodiments, a nucleotide and nucleoside compounds and prodrugs, which show significant efficacy and therapeutic bioavailability such as a human liver cancer. 可以治疗的肝癌包括原发性肝癌和继发性肝癌。 Liver cancer may include the treatment of primary liver cancer and secondary liver cancer. 在具体实施方案中,肝癌是肝细胞癌、胆管细胞型肝癌或胆道癌。 In a particular embodiment, the liver cancer is hepatocellular carcinoma, cholangiocarcinoma or bile duct cancer. 在具体实施方案中,肝癌是肝中起源于其它癌症(例如结肠癌、胰腺癌等)的癌转移。 In a particular embodiment, the liver is the liver originated in other cancers (such as colon, pancreatic, etc.) cancer metastasis. 在某些实施方案中,本文所述的化合物可以用于治疗癌症,例如乳腺癌、卵巢癌、肺癌、胰腺癌和白血病癌。 In certain embodiments, the compounds described herein may be used for the treatment of cancer, such as breast cancer, ovarian cancer, lung cancer, pancreatic cancer and leukemia.

[0003] 发明背景 [0003] Background of the Invention

[0004] 癌症是一种特征主要在于来源于特定正常组织的异常细胞不受控制地进行分裂并且这些恶性细胞侵入相邻组织的疾病。 [0004] Cancer is a major feature in that the abnormal cells derived from a particular normal tissue divide and uncontrolled invasion of these malignant cells adjacent diseased tissue. 血液或淋巴输送会将癌细胞传播至身体其它部分,引到局部淋巴结和远的部位(转移)。 Transporting the blood or lymphatic cancer will spread to other parts of the body, lead to the regional lymph nodes and distant sites (metastasis). 癌症是一个复杂的多步过程,其是从微小的肿瘤前改变开始,这些肿瘤前改变在一定条件下可能进展到肿瘤形成。 Cancer is a complex, multi-step process that is beginning to change from the front of the tiny tumor, change under certain conditions may progress to tumor formation before these tumors. 存在超过100个不同类型的癌症,其可以分组成较广泛的种类。 The presence of more than 100 different types of cancer, which can be grouped into broader categories. 主要种类包括:癌瘤、肉瘤、白血病、淋巴瘤和骨髓瘤,以及中枢神经系统癌症。 The main categories include: carcinoma, sarcoma, leukemia, lymphoma and myeloma, and central nervous system cancer. 癌症的发生率随着总人口的年龄、新癌症的发展以及易感人群(例如感染上艾滋病或过度暴露于日光的人)的增长而不断地上升。 The incidence of cancer increases with age population, as well as the development of new cancer susceptible populations (such as infection with HIV or excessive exposure to sunlight people) growth and constantly rising. 因此,非常需要可以用于治疗癌症患者的新方法和组合物。 Therefore, it is necessary, for new methods and compositions for treating cancer patients.

[0005] 血液系统或造血系统恶性肿瘤是血液或骨髓的癌症,包括白血病和淋巴瘤。 [0005] hematopoietic malignancies or hematologic blood or bone marrow cancers, including leukemias and lymphomas. 白血病是一种特征在于不成熟的白血球异常地积累的血液癌症。 Characterized in that the leukemia is an abnormal accumulation of immature white blood cells of blood cancer. 存在四种类型白血病:急性淋巴细胞性白血病(acute lymphocytic leukemia,ALL)、急性髓细胞性白血病(acute myelogenous leukemia,AML)、慢性淋巴细胞性白血病(chronic lymphocytic leukemia, CLL)和慢性髓细胞性白血病(chronic myelogenous leukemia,CML)。 There are four types of leukemia: Acute lymphocytic leukemia (acute lymphocytic leukemia, ALL), acute myeloid leukemia (acute myelogenous leukemia, AML), chronic lymphocytic leukemia (chronic lymphocytic leukemia, CLL) and chronic myelogenous leukemia (chronic myelogenous leukemia, CML). 急性白血病是一种进展迅速的疾病,其导致不成熟的无功能细胞积累在骨髓和血液中。 Acute leukemia is a disease of rapid progress, which results in the accumulation of immature non-functional cells in the bone marrow and blood. 骨髓常常停止产生足够的正常红细胞、白细胞和血小板。 Bone marrow often stops generating sufficient normal erythrocytes, leukocytes and platelets. 另一方面,慢性白血病进展较慢,并允许制造出更大数目的更成熟的功能细胞。 On the other hand, chronic leukemia is slow progress, and allows for more sophisticated functions produce a greater number of cells.

[0006] 白血病可以影响任何年龄的人。 [0006] Leukemia can affect people of any age. 大部分白血病病例的病因是未知的。 Most of the cases the cause of leukemia is unknown. 异常剂量的辐射和某些癌症疗法可能是病因。 Abnormal doses of radiation and certain cancer therapies may be the cause. 约90%的白血病是在成年人中诊断出。 About 90% of leukemia is diagnosed in adults. 慢性白血病的病例比急性白血病病例多4.5 %。 More cases of chronic leukemia acute leukemia cases 4.5%. 成年人中最常见的白血病类型是急性髓细胞性白血病(AML),据估计2013年有14,590例新病例;以及慢性淋巴细胞性白血病(CLL),2013年约有15,680例新病例。 Adults, the most common type of leukemia is acute myeloid leukemia (AML), it is estimated that there are 14,590 new cases in 2013; and chronic lymphocytic leukemia (CLL), 2013 Nian about 15,680 new cases. 据估计在2013年,慢性髓细胞性白血病(CML)影响约5,920个人(数据来自the Leukemia and Lymphoma Society,Facts 2013,2013年8月)。 It is estimated that in 2013, chronic myelogenous leukemia (CML) affects approximately 5,920 individuals (data from the Leukemia and Lymphoma Society, Facts 2013, 2013 Nian August).

[0007] 在20世纪下半叶,血液癌症治疗上的巨大改善基本上是化学疗法带来的。 [0007] In the second half of the 20th century, a huge improvement in the treatment of blood cancer is basically caused by chemotherapy. 另外,存在超过50种个别地用于治疗这些病症的药物并且许多潜在的新疗法正在临床试验中。 In addition, there are more than 50 kinds of drugs used individually to treat these conditions and many potential new therapies in clinical trials. 虽然当前化学疗法可以完全缓解白血病,但白血病、尤其是AML的长期无病存活率较低。 Although the current chemotherapy can complete remission of leukemia, but leukemia, especially low long-term disease-free survival of AML. 举例来说,据估计,从2003年至2009年,AML的总体相对存活率是约59%。 For example, it is estimated that from 2003 to 2009, the overall relative survival rate for AML is about 59%. 因此,对用于治疗包括白血病在内的血液癌症的有效治疗剂的需要是很显然的并且尚未得到满足。 Therefore, the need for effective therapeutic agents for the treatment of blood cancers including leukemia's and is apparently not yet been met.

[0008] 原发性肝癌是世界上最常见的一种癌症形式。 [0008] Primary liver cancer is the most common form of cancer form. 肝细胞癌又名恶性肝癌,是最常见的原发性肝癌形式,并且在肝细胞内发展。 Hepatocellular carcinoma, also known as malignant liver cancer is the most common form of primary liver cancer, and to develop in the liver cells. 肝细胞癌主要发生在男性和患有肝硬化的患者中。 HCC occurs mainly in men and in patients suffering from liver cirrhosis. 它已经成为全世界癌症死亡的第三大原因(Block TM等人,2003,0ncogene 22:5093-5107)。 It has become the third leading cause (Block TM et al., 2003,0ncogene 22: 5093-5107) of cancer deaths worldwide. 许多患有肝细胞癌的患者直到疾病处于晚期才出现症状,从而导致治疗无效和预后不良;大多数的无法进行切除的肝细胞癌患者在一年内死亡。 Many patients with hepatocellular carcinoma until the disease is in late stage symptoms, leading to ineffective treatment and poor prognosis; the majority of patients with hepatocellular carcinoma can not be cut die within a year.

[0009] 肝细胞癌的治疗选择受到限制,特别是在晚期或复发性肝细胞癌的情况下。 Treatment Options [0009] HCC is limited, especially in the case of advanced and recurrent hepatocellular carcinoma. 外科手术和放射疗法是早期肝癌的选择,但对于晚期或复发性肝细胞癌来说不是特别有效。 Surgery and radiation therapy is liver cancer early choice, but not particularly effective for advanced or recurrent hepatocellular carcinoma is. 全身性化学疗法不是特别有效,并且可用的药物数目非常有限。 Systemic chemotherapy is not particularly effective, and the number of drugs available is very limited. 最近批准的激酶抑制剂索拉非尼(sorafenib)已经显示有效治疗肝细胞癌。 The recently approved kinase inhibitor sorafenib (sorafenib) has been shown effective in treating hepatocellular carcinoma. 但是,其只能减缓或阻止晚期肝癌进展,比无治疗情况下长几个月。 However, it can only slow or stop the progression of advanced liver cancer, compared with no treatment long months.

[0010] 需要用于治疗或预防癌症的新疗法。 [0010] need for new therapies to treat or prevent cancer. 发明概要 SUMMARY OF THE INVENTION

[0011] 本文提供了可用于例如治疗癌症,例如肝癌的化合物。 [0011] Provided herein are useful for example in the treatment of cancer, for example, liver cancer compound. 化合物是与前药部分连接的核苷和核苷酸类似物。 Compound is a nucleoside and nucleotide analogs connected to the front portion of the drug. 在某些实施方案中,与前药部分连接的核苷和核苷酸类似物可以显示治疗人类癌症,例如肝癌的显著功效或生物利用率或者两者。 In certain embodiments, the prodrug moiety is connected to the nucleoside and nucleotide analogs may display treatment of human cancers, liver cancer, for example, significant efficacy or bioavailability or both. 可以治疗的肝癌包括原发性肝癌和继发性肝癌。 Liver cancer may include the treatment of primary liver cancer and secondary liver cancer. 在具体实施方案中,肝癌是肝细胞癌、胆管细胞型肝癌或胆道癌。 In a particular embodiment, the liver cancer is hepatocellular carcinoma, cholangiocarcinoma or bile duct cancer. 在具体实施方案中,肝癌是肝中起源于其它癌症(例如结肠癌、胰腺癌等)的癌转移。 In a particular embodiment, the liver is the liver originated in other cancers (such as colon, pancreatic, etc.) cancer metastasis. 在某些实施方案中,本文所述的化合物可以用于治疗癌症,例如乳腺癌、卵巢癌、肺癌、胰腺癌和白血病癌。 In certain embodiments, the compounds described herein may be used for the treatment of cancer, such as breast cancer, ovarian cancer, lung cancer, pancreatic cancer and leukemia.

[0012] 在某些实施方案中,本文提供的化合物可用于预防和治疗癌症,例如肝癌,例如肝细胞癌、胆管细胞型肝癌或胆道癌。 [0012] In certain embodiments, the compounds provided herein are useful for the prevention and treatment of cancer, such as liver cancer, for example hepatocellular carcinoma, cholangiocarcinoma or bile duct cancer. 这些化合物或制剂还可以预防性地用于预防或延迟具有癌症,例如肝癌,例如肝细胞癌、胆管细胞型肝癌或胆道癌的症状的个体中临床疾病的进展。 These compounds or formulations can also be used prophylactically to prevent or delay having a cancer, such as liver cancer, the individual progress e.g. hepatocellular carcinoma, cholangiocarcinoma or bile duct cancer in the clinical symptoms of the disease. 在某些实施方案中,本文所述的化合物或制剂可以用于治疗癌症,例如乳腺癌、卵巢癌、 肺癌、胰腺癌和白血病癌。 In certain embodiments, the compounds described herein, or formulations can be used for the treatment of cancer, such as breast cancer, ovarian cancer, lung cancer, pancreatic cancer and leukemia.

[0013] 还提供了一种用于治疗例如人类的受试者中癌症,例如肝癌,例如肝细胞癌、胆管细胞型肝癌或胆道癌或者肝中起源于其它癌症(例如结肠癌、胰腺癌等)的癌转移的方法, 所述方法包括施用任选地于药学上可接受的载体中的有效量的本文提供的化合物,单独施用或与另一抗癌药剂组合或交替施用。 [0013] also provides a method for treating cancer in a subject such as a human, such as liver cancer, for example hepatocellular carcinoma, cholangiocarcinoma, or liver or biliary tract cancer originated in other cancers (such as colon, pancreatic ) a method of cancer metastasis, said method comprising administering a compound optionally in a pharmaceutically acceptable carrier in an effective amount provided herein, administered alone or with another anticancer agent is administered in combination or alternation. 在某些实施方案中,癌症选自乳腺癌、卵巢癌、肺癌、 胰腺癌和白血病癌。 In certain embodiments, the cancer is selected from breast cancer, ovarian cancer, lung cancer, pancreatic cancer and leukemia.

[0014] 本文提供了根据式I的化合物: [0014] Provided herein are compounds according to formula I:

[0015] [0015]

Figure CN108368147AD00071

[0016] 或其药学上可接受的盐,其中: [0016] or a pharmaceutically acceptable salt thereof, wherein:

[0017] R1与R2中的一个是氢并且另一个是 [0017] R1 and R2 is hydrogen and the other is a

[0018: [0018:

Figure CN108368147AD00081

[0019]或R1和R2连同其连接的两个氧原子一起形成以下环结构: [0019] or R1 and R2 together with the two oxygen atoms connected to form the following ring structure:

[002C [002C

Figure CN108368147AD00082

[0021] R3是氢、Ckq烷基、C2-n烯基、C2-n炔基、Ckq烷氧基羰基Ckq烷基、Ckq烷基羰基硫基C1-K)烷基、C1-K)烷基二硫基&-6烷基、芳基或杂芳基C1-K)烷基,其中烷基任选地经一个、两个或三个独立选自卤素和羟基的取代基取代,并且杂芳基经一个或两个选自Cho烷基和硝基的取代基取代; [0021] R3 is hydrogen, Ckq alkyl, C2-n alkenyl, C2-n alkynyl, Ckq CKQ alkoxycarbonyl group, Ckq alkylcarbonyl group C1-K) alkyl, C1-K) alkoxy disulfide group & amp; -6 alkyl, aryl or heteroaryl C1-K) alkyl, wherein alkyl is optionally substituted with one, two or three substituents independently selected from halogen and hydroxy, and heteroaryl substituted with one or two alkyl groups selected Cho and nitro substituents;

[0022] R4是氢或C1-K)烷基; [0022] R4 is hydrogen or C1-K) alkyl;

[0023] R5是Cl-IQ烧氧基幾基、C3-1Q环烧氧基幾基、Cl-IQ烧基幾氧基Cl-IQ烧基、C3-1Q环烧基幾氧基、芳基、芳氧基、C1-K)烷基芳基、芳基C1-K)烷基、芳基C1-K)烷氧基羰基、芳氧基羰基、杂芳基、杂芳基C1-K)烷基或C1-K)烷基杂芳基; [0023] R5 is Cl-IQ group burning several groups, C3-1Q cycloalkyl group fired several groups, Cl-IQ group burn burn Cl-IQ several yloxy group, C3-1Q cycloalkyl group fired several group, an aryl group , aryloxy, C1-K) alkyl aryl, aryl-C1-K) alkyl, aryl C1-K) alkoxycarbonyl group, an aryloxycarbonyl group, a heteroaryl group, heteroaryl C1-K) alkyl or C1-K) alkyl heteroaryl;

[0024] R6是 [0024] R6 is

[0025] [0025]

Figure CN108368147AD00083

或-OR3;并且 Or -OR3; and

[0026] W是喊S, [0026] W is shouting S,

[0027] 条件是不包括下式化合物: [0027] with the proviso that a compound of the formula:

[0028] [0028]

Figure CN108368147AD00084

[0029] 其中R3'是芳基或任选取代的杂芳基,R4'是&-1()烷基,!^是心巧烷基、C3-1Q环烷基、芳基C1-K)烷基或芳基,并且W是0。 [0029] wherein R3 'is aryl or optionally substituted heteroaryl, R4' is & amp; -1 () alkyl, heart clever ^ alkyl, C3-1Q cycloalkyl, aryl C1-K! ) alkyl or aryl, and W is 0.

[0030] 在一个实施方案中,不包括下式化合物: [0030] In one embodiment, not including the compound of the formula:

[0031; [0031;

Figure CN108368147AD00091

[0032] 其中R3是芳基或任选取代的杂芳基,R4是C1-K)烷基,RfCH烷基、C3-1Q环烷基、芳基C1-K)烷基或芳基,并且W是0或S。 [0032] wherein R3 is an optionally substituted aryl or heteroaryl, R4 is C1-K) alkyl, RfCH alkyl, C3-1Q cycloalkyl, aryl C1-K) alkyl or aryl, and W is 0 or S.

[0033] 在一个方面中,本文提供的化合物与第二治疗剂,例如可用于治疗或预防癌症的治疗剂组合提供或施用。 [0033] In one aspect, the compound provided herein and the second therapeutic agent, for example, can be used in combination therapeutic agent for treating or preventing cancer or provide administration. 本文中的其它地方详细地提供示例性第二治疗剂。 Provided elsewhere herein in detail exemplary second therapeutic agent.

[0034] 在另一方面中,本文提供了适用于治疗或预防例如癌症,例如肝癌的病症的药物组合物、单一单位剂型和试剂盒,其包含治疗或预防有效量的本文提供的化合物,例如式I-VIII化合物,和治疗或预防有效量的第二治疗剂,例如可用于治疗或预防癌症,例如肝癌的治疗剂。 [0034] In another aspect, it provided herein are compounds useful for treating or preventing cancer, e.g., a liver condition, for example, pharmaceutical compositions, single unit dosage forms, and kits comprising a therapeutically or prophylactically effective amount of the herein provided, e.g. the compounds of formula I-VIII, and treating or preventing effective amount of a second therapeutic agent, for example, for the treatment or prevention of cancer, such as liver cancer therapeutic agent. 在某些实施方案中,癌症选自乳腺癌、卵巢癌、肺癌、胰腺癌和白血病癌。 In certain embodiments, the cancer is selected from breast cancer, ovarian cancer, lung cancer, pancreatic cancer and leukemia.

[0035] 在某些实施方案中,提供了一种治疗肝病的方法,所述方法包括向有需要的个体施用治疗有效量的本文所述的化合物。 [0035] In certain embodiments, there is provided a method of treating liver disease, said method comprising administering a compound described herein to treat an individual in need thereof an effective amount of a.

[0036] 可以治疗的肝癌包括原发性肝癌和继发性肝癌。 [0036] liver cancer may be treated include primary liver cancer and secondary liver cancer. 在具体实施方案中,肝癌是肝细胞癌、胆管细胞型肝癌或胆道癌。 In a particular embodiment, the liver cancer is hepatocellular carcinoma, cholangiocarcinoma or bile duct cancer.

[0037] 发明详述 [0037] DETAILED DESCRIPTION

[0038] 本文提供了可用于治疗受试者的癌症的化合物、组合物和方法。 [0038] Provided herein are compounds useful for treating cancer in a subject, the compositions and methods. 进一步提供了可用于这类方法的剂型。 Further dosage forms can be used provided such processes. 在某些实施方案中,癌症选自肝癌、乳腺癌、卵巢癌、肺癌、胰腺癌和白血病癌。 In certain embodiments, the cancer is selected from cancer, breast cancer, ovarian cancer, lung cancer, pancreatic cancer and leukemia.

[0039] 定义 [0039] defined

[0040] 当提及本文提供的化合物时,除非另外指示,否则以下术语具有以下含义。 [0040] When referring to the compounds provided herein, unless otherwise indicated, the following terms have the following meanings. 除非另外定义,否则本文中使用的所有技术和科学术语具有与本领域的一般技术人员通常所了解的含义相同的含义。 Unless defined otherwise, all technical and scientific terms used herein have the same meaning as those of ordinary skill in the art as commonly understood. 如果本文中术语存在多个定义,那么除非另有说明,否则以本节中的定义为准。 If there are multiple definitions of the terms used herein, then, unless otherwise specified, to the definition in this section shall prevail.

[0041] 除非另作说明,否则如本文所用的术语“烷基”是指饱和直链或支链烃。 [0041] Unless indicated otherwise, as used herein, the term "alkyl" refers to a saturated straight or branched chain hydrocarbon. 在某些实施方案中,烷基是伯烃、仲烃或叔烃。 In certain embodiments, the alkyl hydrocarbon is a primary, secondary, or tertiary hydrocarbon hydrocarbons. 烷基包括一个至十个碳原子,即(^至^。烷基。在一个实施方案中,烷基包括一个至六个碳原子,即&至〇5烷基。在某些实施方案中,烷基是甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、异戊基、新戊基、己基、异己基、3-甲基戊基、2,2-二甲基丁基或2,3-二甲基丁基。 Alkyl group comprising one to ten carbon atoms, i.e., (alkyl ^ ^ to one embodiment, the alkyl group comprising one to six carbon atoms, i.e., & amp;... To 〇5 alkyl In certain embodiments alkyl group is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, 3- methylpentyl, 2,2-dimethylbutyl or 2,3-dimethylbutyl.

[0042] 除非另作说明,否则如本文所用的术语“环烷基”是指饱和环烃。 [0042] Unless indicated otherwise, as used herein, the term "cycloalkyl" means a saturated cyclic hydrocarbon. 在某些实施方案中,环烷基可以是饱和和/或桥环和/或非桥环和/或稠合双环基团。 In certain embodiments, the cycloalkyl group may be saturated and / or bridged rings and / or non-bridged and / or fused bicyclic groups. 环烷基包括三个至十个碳原子,即C3至Ciq环烷基。 A cycloalkyl group comprising three to ten carbon atoms, i.e., cycloalkyl C3 to Ciq. 在一些实施方案中,环烷基具有3至15个(C3-15)、3至10个(C3-1Q)或3至7个(C3-7)碳原子。 In some embodiments, a cycloalkyl group having 3 to 15 (C3-15), 3 to 10 th (C3-1Q) or 3-7 (the C3-7) carbon atoms. 在某些实施方案中,环烷基是环丙基、环丁基、环戊基、环己基、环己基甲基、环庚基、二环[2.1.1]己基、二环[2.2.1]庚基、萘烷基或金刚烷基。 In certain embodiments, cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexylmethyl, cycloheptyl, bicyclo [2.1.1] hexyl, bicyclo [2.2.1 ] heptyl, naphthyl or adamantyl.

[0043] 术语“烯基”是指单价烯系不饱和烃基,其具有2个至11个碳原子,包括2个至8个碳原子或2个至6个碳原子,可以是直链或支链并且具有至少1个,包括1个至2个烯系不饱和位点。 [0043] The term "alkenyl" refers to a monovalent olefinically unsaturated hydrocarbon group having 2-11 carbon atoms, comprising 2 to 8 carbon atoms or 2 to 6 carbon atoms, may be straight chain or branched and having at least one chain, comprising from 1 to 2 sites of olefinic unsaturation. 示例性烯基包括乙烯基(即乙烯基或-CH=CH2)、正丙烯基(-CH2CH=CH2)、异丙烯基(-C (CH3) =CH2)等等。 Exemplary alkenyl groups include ethenyl (i.e., vinyl or -CH = CH2), n-propenyl (-CH2CH = CH2), isopropenyl (-C (CH3) = CH2) and the like.

[0044] 术语“炔基”是指炔系不饱和烃基,其具有2个至11个碳原子或2个至6个碳原子,可以是直链或支链并且具有至少1个或1个至2个炔系不饱和位点。 [0044] The term "alkynyl" means an alkynyl unsaturated hydrocarbon radical having 2-11 carbon atoms or 2 to 6 carbon atoms, may be linear or branched and having at least one or one to 2 acetylenic unsaturation. 炔基的非限制性实例包括乙炔、乙炔基(-C=CH)、炔丙基(-CH2C=CH)等等。 Non-limiting examples of alkynyl groups include ethynyl, ethynyl (-C = CH), propargyl (-CH2C = CH) and the like.

[0045] 如本文所用并且除非另作说明,术语“芳基”是指衍生自芳香环的取代基。 [0045] As used herein and unless otherwise indicated, the term "aryl" means a substituent group derived from an aromatic ring. 在一个实施方案中,芳基是C6-C12芳基。 In one embodiment, the aryl group is C6-C12 aryl group. 在一个实施方案中,芳基是苯基、联苯基或萘基。 In one embodiment, the aryl group is phenyl, biphenyl or naphthyl. 在一个实施方案中,芳基是苯基。 In one embodiment, the aryl group is phenyl.

[0046] uC1-K)烷氧基(Cwoalkoxy)”和uC1-K)烷氧基(Ci-ioalkoxyl)”是指基团-ΟΥ,其中IT 是如本文中所定义的烷基。 [0046] uC1-K) alkoxy (Cwoalkoxy) "and uC1-K) alkoxy (Ci-ioalkoxyl)" refers to the group -ΟΥ, where IT is an alkyl group as defined herein. 烷氧基是-OR/,其中R/是烷基,并且其中烷基是(^至^。烷基。烷氧基包括例如甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、叔丁氧基、仲丁氧基、正戊氧基、正己氧基、1,2_二甲基丁氧基等等。 Alkoxy is -OR /, wherein R / is an alkyl group, and wherein alkyl is (^ to ^ alkyl alkoxy group includes, for example, methoxy, ethoxy, n-propoxy, isopropoxy , n-butoxy, tert-butoxy, sec-butoxy, n-pentyloxy, n-hexyloxy, 1,2_-dimethylbutoxy and the like.

[0047] “C3-1Q环烧氧基(C3-iocycloalkoxy)”和“C3-1Q环烧氧基(C3-iocyclolkoxyl)” 是指基团-OR/,其中R/是如本文所定义的环烷基。 [0047] "C3-1Q cycloalkyl group burn (C3-iocycloalkoxy)" and "C3-1Q cycloalkyl group burn (C3-iocyclolkoxyl)" refers to the group -OR /, wherein R / is a ring as defined herein alkyl. 烷氧基是-OR/,其中R/是环烷基,并且其中环烷基是C3至ClQ环烧基。 Alkoxy is -OR /, wherein R / is cycloalkyl and wherein cycloalkyl is a C3 to burn ClQ cycloalkyl group.

[0048] “烷基羰氧基”是指基团-O-C⑼-烷基,其中烷基如本文中所定义。 [0048] "alkylcarbonyloxy" refers to the group -O-C⑼- alkyl, wherein alkyl is as defined herein.

[0049] “环烷基羰氧基”是指基团-O-C⑼-环烷基,其中环烷基如本文中所定义。 [0049] "cycloalkyl carbonyl group" means a group -O-C⑼- cycloalkyl, wherein cycloalkyl is as defined herein.

[0050] “芳氧基”是指基团-0-芳基,其中芳基如本文中所定义。 [0050] "Aryloxy" refers to the group -0- aryl, wherein aryl is as defined herein.

[0051] “烷氧基羰基”是指基团-C⑼-烷氧基,其中烷氧基如本文中所定义。 [0051] "alkoxycarbonyl" refers to the group -C⑼- alkoxy, wherein alkoxy is as defined herein.

[0052] “环烷氧基羰基”是指基团-C⑼-环烷氧基,其中环烷氧基如本文中所定义。 [0052] "cycloalkoxy group" refers to the group -C⑼- cycloalkoxy, cycloalkoxy wherein as defined herein.

[0053] “烷氧基烷基羰基”是指基团-C⑼-烷基-烷氧基,其中烷氧基和烷基如本文中所定义。 [0053] "alkoxyalkyl group" refers to the group alkyl -C⑼- - alkoxy, wherein the alkoxy and alkyl as defined herein.

[0054] “芳基烷氧基羰基”是指基团-C(O)-烷氧基-芳基,其中烷氧基和芳基如本文中所定义。 [0054] "arylalkoxy carbonyl" refers to the group -C (O) - alkoxy - aryl group, wherein the alkoxy and aryl are as defined herein.

[0055] “芳氧基羰基”是指基团-C⑼-0-芳基,其中芳基如本文中所定义。 [0055] "aryloxycarbonyl group" refers to the group -C⑼-0- aryl, wherein aryl is as defined herein.

[0056] “烷氧基羰基烷基”是指基团-烷基-C(O)-烷氧基,其中烷氧基和烷基如本文中所定义。 [0056] "alkoxycarbonyl group" refers to the group - alkyl -C (O) - alkoxy, wherein the alkoxy and alkyl as defined herein.

[0057] “烷氧基羰基烷氧基”是指基团-烷氧基-C(O)-烷氧基,其中烷氧基和烷基如本文中所定义。 [0057] "alkoxycarbonyl alkoxy" refers to the group - alkoxy, -C (O) - alkoxy, wherein the alkoxy and alkyl as defined herein.

[0058] 如本文中所用,“烷基羰氧基烷基”是指基团-烷基-O-C⑼-烷基,其中烷基如本文中所定义。 [0058] As used herein, "alkylcarbonyloxy group" refers to the group - alkyl -O-C⑼- alkyl, wherein alkyl is as defined herein.

[0059] 如本文中所用,“烷基二硫基烷基”是指基团-烷基-SS-烷基,其中烷基如本文中所定义。 [0059] As used herein, "alkyl di alkylthioalkyl" refers to the group - -SS- alkyl group, wherein alkyl is as defined herein.

[0060] 如本文中所用,“烷基羰基硫基烷基”是指基团-烷基-SC(O)-烷基,其中烷基如本文中所定义。 [0060] As used herein, "alkylcarbonyl alkylthioalkyl" refers to the group - alkyl group -SC (O) - alkyl, wherein alkyl is as defined herein.

[0061] “烷基芳基”是指具有烷基取代基的芳基,其中烷基和芳基如本文中所定义。 [0061] "alkylaryl" refers to an aryl group substituted with an alkyl group, wherein alkyl and aryl are as defined herein.

[0062] “芳基烷基”是指具有芳基取代基的烷基,其中烷基和芳基如本文中所定义。 [0062] "Arylalkyl" means an alkyl group having an aryl substituent group, wherein alkyl and aryl are as defined herein.

[0063] “氧代基”是指基团=0。 [0063] "oxo" refers to the group = 0.

[0064] “竣基(Carboxy 1) ” 或“竣基(carboxy) ” 是指基团-C ⑼ 0H。 [0064] "Jun group (Carboxy 1)" or "Jun group (carboxy)" refers to the group -C ⑼ 0H.

[0065] “羰基”是指基团-C⑼。 [0065] "Carbonyl" refers to the group -C⑼.

[0066] “齒素”或“齒基”是指氯基、溴基、氟基或碘基。 [0066] "prime tooth" or "teeth" refers to chloro, bromo, fluoro, or iodo.

[0067] “氨基”是指基团-NR1V或-NR1、其中W和β独立地是氢、烷基、烯基、炔基、环烷基、杂环、芳基或杂芳基,每一个如本文中所定义。 [0067] "Amino" refers to the group -NR1V or -NR1, wherein W and β are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group, each of We are as defined herein. 在一个实施方案中,^和中的每一个独立地是氢或烷基。 In one embodiment, each of a and ^ is independently hydrogen or alkyl. 在一个实施方案中,R1 ^和^中的每一个是氢。 In one embodiment, R1 ^ and a ^ are each hydrogen.

[0068] 术语“杂芳基”是指含有至少一个芳香环的单价单环芳族基和/或多环芳族基,其中至少一个芳香环在环中含有一个或多个独立地选自0、S和N的杂原子。 [0068] The term "heteroaryl" refers to a monovalent monocyclic aromatic group and / or polycyclic aromatic group containing at least one aromatic ring, wherein the at least one aromatic ring containing one or more groups independently selected from 0 in the ring , S and N heteroatoms. 杂芳基通过芳香环键结至分子其余部分。 Heteroaryl bonded through the aromatic ring to the rest of the molecule. 杂芳基的每个环可以含有一个或两个0原子、一个或两个S原子和/或一个至四个N原子,条件是每个环中的杂原子总数是四个或更少并且每个环含有至少一个碳原子。 Each ring of a heteroaryl group may contain one or two 0 atoms, one or two S atoms and / or one to four N atoms provided that the total number of heteroatoms in each ring is four or less and each ring containing at least one carbon atom. 在某些实施方案中,杂芳基具有5个至20个、5个至15个或5个至10个环原子。 In certain embodiments, the heteroaryl group has 5 to 20, 5 to 15 or 5 to 10 ring atoms. 在一个实施方案中,杂芳基具有5个环原子。 In one embodiment, the heteroaryl group has 5 ring atoms. 单环杂芳基的实例包括(但不限于)呋喃基、咪唑基、异噻唑基、异噁唑基、噁二唑基、噁唑基、吡嗪基、吡唑基、哒嗪基、吡啶基、嘧啶基、吡咯基、噻二唑基、噻唑基、噻吩基、四唑基、三嗪基和三唑基。 Examples of monocyclic heteroaryl groups include (but are not limited to) furyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl , pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazinyl, and triazolyl. 双环杂芳基的实例包括(但不限于)苯并呋喃基、苯并咪唑基、苯并异噁唑基、苯并吡喃基、苯并噻二唑基、苯并噻唑基、苯并噻吩基、 苯并三唑基、苯并噁唑基、呋喃并吡啶基、咪唑并吡啶基、咪唑并噻唑基、吲嗪基、吲哚基、吲唑基、异苯并呋喃基、异苯并噻吩基、异吲哚基、异喹啉基、异噻唑基、萘啶基、噁唑并吡啶基、酞嗪基、蝶啶基、嘌呤基、吡啶并吡啶基、吡咯并吡啶基、喹啉基、喹喔啉基、喹唑啉基、噻二唑并嘧啶基和噻吩并吡啶基。 Examples of bicyclic heteroaryl groups include (but are not limited to) benzofuranyl, benzimidazolyl, benzisoxazolyl, benzopyranyl, benzo-thiadiazolyl, benzothiazolyl, benzothienyl group, benzotriazolyl, benzoxazolyl, furanyl and pyridyl, imidazolyl and pyridyl, imidazolyl, and thiazolyl, indolizinyl, indolyl, indazolyl, isobenzofuran-yl, isobenzofuran thienyl, isoindolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxazolyl and pyridyl, phthalazinyl, pteridinyl, purinyl, pyridyl and pyridyl, pyrrolyl and pyridyl, quinolyl group, quinoxalinyl, quinazolinyl, pyrimidinyl and thiadiazolyl, and pyridyl and thienyl. 三环杂芳基的实例包括(但不限于)卩丫啶基、苯并吲哚基、咔唑基、二苯并呋喃基、萘嵌间二氮杂苯基、菲罗啉基、菲啶基、吩舭嗪基、吩嗪基、吩噻嗪基、 吩噁嗪基和氧杂蒽基。 Examples of tricyclic heteroaryl groups include (but are not limited to) Jie acridinyl, benzo indolyl, carbazolyl, dibenzofuranyl group, a phenyl group between perimidine, phenanthroline group, phenanthridinyl, bilge thienyl, piperazinyl, phenazine group, a phenothiazine group, a phenoxazine group and a xanthene group. 在一个实施方案中,杂芳基选自咪唑基、噻唑基、噻吩基和呋喃基。 In one embodiment, the heteroaryl is selected from imidazolyl, thiazolyl, thienyl and furanyl. 在一个实施方案中,杂芳基是N-甲基咪唑基。 In one embodiment, the heteroaryl group is N- methylimidazole. 在某些实施方案中,杂芳基也可以如本文所述被任选地取代。 In certain embodiments, heteroaryl may also be optionally substituted as described herein. 在一个实施方案中,杂芳基经一个硝基和一个甲基取代。 In one embodiment, a heteroaryl group substituted with a nitro group and a methyl group. 在一个实施方案中, 杂芳基经一个硝基取代。 In one embodiment, a heteroaryl group substituted with a nitro group.

[0069] 术语“杂芳基烷基”是指具有杂芳基取代基的烷基。 [0069] The term "heteroarylalkyl" means an alkyl group substituted with a heteroaryl group.

[0070] 术语“烷基杂芳基”是指具有烷基取代基的杂芳基。 [0070] The term "alkylheteroaryl" refers to an alkyl group substituted with a heteroaryl group.

[0071] 如本文所用并且除非另外定义,否则术语“保护基”是指加到氧原子、氮原子或磷原子上以防这些原子进一步反应或实现其它目的的基团。 [0071] As used herein and unless otherwise defined, the term "protecting group" refers to prevent further reaction of these atoms or groups to achieve the other objects added to an oxygen atom, a nitrogen atom or a phosphorus atom. 有机合成领域的技术人员已知多种氧保护基和氮保护基。 Skilled in the art of organic synthesis known oxygen protecting group and various nitrogen protecting group.

[0072] “药学上可接受的盐”是指本文提供的化合物的任何盐,其保留化合物的生物性质并且对于药用来说无毒或在其它方面没有不合需要。 [0072] "Pharmaceutically acceptable salt" refers to any salt of a compound provided herein, which retain the biological properties of the compound and is nontoxic for pharmaceutical or not undesirable in other respects. 这类盐可以衍生自本领域中众所周知的多种有机抗衡离子和无机抗衡离子。 Such salts may be derived from a variety of well known in the art of organic counterions and inorganic counterions. 这类盐包括(但不限于):(1)用有机酸或无机酸形成的酸加成盐,所述有机酸或无机酸例如盐酸、氢溴酸、硫酸、硝酸、磷酸、氨基磺酸、乙酸、三氟乙酸、三氯乙酸、丙酸、己酸、环戊基丙酸、乙醇酸、戊二酸、丙酮酸、乳酸、丙二酸、琥珀酸、 山梨酸、抗坏血酸、苹果酸、顺丁烯二酸、反丁烯二酸、酒石酸、柠檬酸、苯甲酸、3-(4-羟基苯甲酰基)苯甲酸、苦味酸、肉桂酸、扁桃酸、邻苯二甲酸、月桂酸、甲烷磺酸、乙烷磺酸、1,2_乙烷-二磺酸、2-羟基乙烷磺酸、苯磺酸、4-氯苯磺酸、2-萘磺酸、4-甲苯磺酸、樟脑酸、樟脑磺酸、4-甲基双环[2.2.2]-辛-2-烯-1-甲酸、葡庚糖酸、3-苯基丙酸、三甲基乙酸、叔丁基乙酸、月桂基硫酸、葡糖酸、苯甲酸、谷氨酸、羟萘甲酸、水杨酸、硬脂酸、环己基氨基磺酸、奎宁酸、粘康酸等酸;或⑵当母体化合物中存在的 Such salts include (but are not limited to) :( 1) acid addition salts formed with an organic or inorganic acid, the organic or inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, sulfamic acid, acetic acid, trifluoroacetic acid, trichloroacetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, glutaric acid, pyruvic acid, lactic acid, malonic acid, succinic acid, sorbic acid, ascorbic acid, malic acid, cis maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3- (4-hydroxybenzoyl) benzoic, picric, cinnamic, mandelic, phthalic, lauric, methanesulfonic acid, ethanesulfonic acid, ethane-1,2_ - disulfonic acid, 2-hydroxy ethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphoric acid, camphorsulfonic acid, 4-methyl-bicyclo [2.2.2] - oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, t-butyl acetate, lauryl sulfuric acid, gluconic acid, benzoic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, cyclohexyl sulfamic acid, quinic acid, muconic acid and the like acids; or when the parent compound ⑵ of 性质子(a)被例如碱金属离子、碱土金属离子或铝离子等金属离子或者例如氢氧化钠、氢氧化钾、氢氧化钙、氢氧化镁、氢氧化铝、氢氧化锂、氢氧化锌和氢氧化钡等碱金属或碱土金属氢氧化物、氨置换或(b)与有机碱,例如脂肪族、脂环族或者芳香族有机胺,例如氨、甲胺、二甲胺、二乙胺、甲基吡啶、乙醇胺、二乙醇胺、三乙醇胺、乙二胺、赖氨酸、精氨酸、鸟氨酸、胆碱、N,N~二苯甲基乙二胺、氯普鲁卡因、 二乙醇胺、普鲁卡因、N-苯甲基苯乙胺、N-甲基葡糖胺、昵嗪、tris(轻甲基)-氨基甲烷、氢氧化四甲铵等配位时所形成的碱加成盐。 Protons (a) is a metal ion, for example, an alkali metal ion, an alkaline earth metal ion or an aluminum ion or the like such as sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, aluminum hydroxide, lithium hydroxide, zinc hydroxide, and barium hydroxide, alkali metal or alkaline earth metal hydroxides, ammonia, substitution or (b) with an organic base, such as aliphatic, alicyclic or aromatic organic amines such as ammonia, methylamine, dimethylamine, diethylamine, picoline, ethanolamine, diethanolamine, triethanolamine, ethylenediamine, lysine, arginine, ornithine, choline, N, N ~ dibenzylethylenediamine, chloroprocaine, di- ethanolamine, procaine, N- benzyl-phenethylamine, N- methylglucamine, piperazine Nick, Tris (light meth) - time base aminomethane, tetramethylammonium hydroxide, and the like of the formed ligand addition salts.

[0073] 药学上可接受的盐进一步包括(仅仅例如并且不限于)钠、钾、钙、镁、铵、四烷基铵等,并且当化合物含有碱性官能团时,包括无毒有机酸或无机酸的盐,例如氢卤酸盐、例如盐酸盐和氢溴酸盐、硫酸盐、磷酸盐、氨基磺酸盐、硝酸盐、乙酸盐、三氟乙酸盐、三氯乙酸盐、丙酸盐、己酸盐、环戊基丙酸盐、乙醇酸盐、戊二酸盐、丙酮酸盐、乳酸盐、丙二酸盐、琥珀酸盐、山梨酸盐、抗坏血酸盐、苹果酸盐、顺丁烯二酸盐、反丁烯二酸盐、酒石酸盐、柠檬酸盐、苯甲酸盐、3- (4-羟基苯甲酰基)苯甲酸盐、苦味酸盐、肉桂酸盐、扁桃酸盐、邻苯二甲酸盐、月桂酸盐、甲烷磺酸盐(甲磺酸盐)、乙烷磺酸盐、1,2-乙烷-二磺酸盐、2-羟基乙烷磺酸盐、苯磺酸盐(苯磺酸盐)、4-氯苯磺酸盐、2-萘磺酸盐、4-甲苯磺酸盐、樟脑酸盐、樟脑磺酸盐、4-甲基双环[2. [0073] Pharmaceutically acceptable salts further comprise (only one example and without limitation) the sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium and the like, and when the compound contains a basic functional group, including non-toxic organic or inorganic acids, for example hydrohalic acid salts such as hydrochloride and hydrobromide, sulfate, phosphate, sulfamate, nitrate, acetate, trifluoroacetate, trichloroacetate, propionate, hexanoate, cyclopentyl propionate, glycolate, glutarate, pyruvate, lactate, malonate, succinate, sorbate, ascorbate, malate salts, maleate, fumarate, tartrate, citrate, benzoate, 3- (4-hydroxybenzoyl) benzoate, picrate, cinnamate , mandelate, phthalate, laurate, methanesulfonate (mesylate), ethanesulfonate, 1,2-ethane - disulfonate, 2-hydroxyethanesulfonate sulfonate, benzenesulfonate (besylate), 4-chlorobenzene sulfonate, 2-naphthalenesulfonate, 4- toluenesulfonate, camphorate, camphorsulfonate, 4-methyl bicyclo [2. 2.2]-辛-2-烯-1-甲酸盐、葡庚糖酸盐、3-苯基丙酸盐、三甲基乙酸盐、叔丁基乙酸盐、月桂基硫酸盐、葡糖酸盐、苯甲酸盐、谷氨酸盐、羟萘甲酸盐、水杨酸盐、硬脂酸盐、环己基氨基磺酸盐、奎宁酸盐、粘康酸盐等。 2.2] - oct-2-ene-1-carboxylic acid, glucoheptonate, 3-phenylpropionate, pivalate, t-butyl acetate, lauryl sulfate, gluconate formate, benzoate, glutamate, hydroxynaphthoate, salicylate, stearate, cyclohexyl sulfamate, quinine salts, muconic acid and the like.

[0074] 除非明确地相反陈述,否则链或环中的任何原子上允许所提及的取代基进行取代,条件是这类取代是化学上允许的并产生稳定的化合物。 [0074] Unless expressly stated to the contrary, or allow any atom on the chain or ring substituents mentioned substituent, provided that such substitution is chemically allowed and results in a stable compound. “稳定”化合物是可以制备和分离并且在足够允许使用化合物达成本文所述的目的(例如治疗或预防施用于受试者)一段时间以后结构和性质保持或可以保持基本上未改变的化合物。 "Stable" compound is prepared and isolated and is sufficient to allow the compound to reach a purpose described herein (e.g., therapeutic or prophylactic administration to a subject) after a period of time or the holding structure and properties of the compounds may remain substantially unchanged.

[0075] 在取代基和取代基模式使得本文所述的化合物中存在互变异构体(例如酮-烯醇互变异构体)的情况下,这些化合物的所有互变异构形式,无论是个别存在还是呈混合物存在,都在本公开的范围内。 [0075] in the presence of compounds of substituents and substituent patterns such that the methods described herein tautomers (e.g. keto - enol tautomer) of the case, all tautomeric forms of these compounds, whether was present or individual mixtures, are within the scope of the present disclosure. 应了解在芳香杂环的碳原子上具有羟基取代基的本公开的化合物包括仅仅存在羟基的化合物、仅仅存在互变异构酮形式(即氧代基取代基)的化合物以及同时存在酮形式和烯醇形式的化合物。 The compounds of this disclosure should be understood that there is only a compound including a hydroxyl group, there is only a mutual tautomeric keto form (i.e. oxo substituent) and a compound exist keto form and having a hydroxy substituent on a carbon atom of an aromatic heterocyclic ring enol form of the compound.

[0076] 如本文所用,当提及核苷的糖环上的取代基时,术语“β”是指与5/碳在糖环平面同一侧上的取代基,并且术语“α”是指与5/碳在糖环平面对侧上的取代基。 [0076] As used herein, when the substituent on the nucleoside sugar ring mentioned, the term "β" refers to a 5 / carbon substituent group is on the same side in the plane of the sugar ring, and the term "α" refers to 5 / carbon sugar ring substituents on opposite sides of the plane. 如下文所示,相对于5 /碳,取代基“Α”处于V'位,并且取代基“Β”处于“β”位: As shown below, with respect to the 5 / carbon, a substituent "Α" in V 'position, and the substituent "Β" in the "β" position:

[0077] [0077]

Figure CN108368147AD00121

.〇 .〇

[0078] 术语“基本上不含”或“基本上缺少”在结合物品(包括(但不限于)化合物、其盐、其溶剂化物、其固体形式等)使用时是指所述物品包括至少85重量%或90重量%,在某些实施方案中,95重量%、98重量%、99重量%或100重量%的指定物品。 [0078] The term "substantially free" or "substantially lacks" in conjunction with articles (including (but not limited to) the compound, a salt thereof, a solvate thereof, in solid form, etc.) refers to the use article comprises at least 85 wt.% or 90 wt%, in some embodiments, 95 wt%, 98 wt%, 99 wt% or 100 wt% of the specified object. 举例来说,关于核苷组合物的术语“基本上不含”或“基本上缺少”可以指核苷组合物包括至少85重量%或90重量%, 在某些实施方案中,95重量%、98重量%、99重量%或100重量%的所述核苷的指定立体异构体。 For example, regarding the term nucleoside composition that "substantially free" or "substantially lacks" may refer to a nucleoside composition that comprises at least 85 wt%, or 90 wt%, in certain embodiments, 95% by weight, 98 wt%, 99 wt% or the 100% by weight of the nucleoside designated stereoisomer. 在某些实施方案中,在本文提供的方法和化合物中,化合物基本上不含未指定的立体异构体或其它化合物。 In certain embodiments, the methods and compounds provided herein, the compound is substantially free of the unspecified other compounds or stereoisomers. 再举例来说,关于固体形式的术语“基本上不含”或“基本上缺少”可以指固体形式包括至少85重量%或90重量%,在某些实施方案中,95重量%、98重量%、99 重量%或100重量%的指定固体形式。 As another example, the term on solid "substantially free" or "substantially lacks" may refer to a solid form comprising at least 85 wt%, or 90 wt%, in some embodiments, 95 wt%, 98 wt% , 99% or 100% by weight of solids of the specified form. 在某些实施方案中,在本文提供的方法和化合物中, 固体形式基本上不含其它固体形式。 In certain embodiments, the compounds and methods provided herein, the solid form is substantially free of other solid forms.

[0079] 类似地,关于核苷组合物的术语“分离”是指核苷组合物包括至少85重量%、90重量%、95重量%、98重量%或99重量%至100重量%的核苷,其余包含其它化学物质或立体异构体。 [0079] Similarly, the term nucleoside composition on "isolated" refers to a nucleoside composition that comprises at least 85 wt%, 90 wt%, 95 wt%, 98 wt%, or 99 wt% to 100 wt% of nucleoside the remainder comprising other chemical species or stereoisomer thereof. 类似地,关于化合物的固体形式,术语“分离”是指固体包括至少85重量%、90重量%、95重量%、98重量%或99重量%至100重量%的化合物的这类固体形式,其余包含化合物的其它固体形式、其它化合物、溶剂和/或其它杂质。 Similarly, with respect to the solid compound, the term "isolated" refers to a solid comprising at least 85 wt%, 90 wt%, 95 wt%, 98 wt% or 99 wt.% Of such compounds in solid form to 100% by weight, the remainder other solid forms containing the compound, other compounds, solvents and / or other impurities.

[0080] “溶剂化物”是指进一步包括通过非共价分子间力结合的化学计算或非化学计算量的溶剂的本文提供的化合物或其盐。 [0080] "Solvate" refers herein further comprises a chemical solvent, is calculated by non-covalent intermolecular forces or non-stoichiometric amount of a provided compound or a salt thereof. 在溶剂是水的情况下,溶剂化物是水合物。 In the case where the solvent is water, the solvate is a hydrate.

[0081] “同位素组成”是指特定原子所存在的每种同位素的量,并且“天然同位素组成”是指特定原子的天然存在的同位素组成或丰度。 [0081] "isotopic composition" refers to the amount of each isotope present in the particular atom, and the "natural isotopic composition" refers to a natural isotopes of atoms present in a particular composition or abundance. 含有其天然同位素组成的原子在本文中也可以称为“非富集”原子。 Atoms which contains natural isotopic composition may also be referred to herein as "non-enriched" atoms. 除非另外指定,否则本文中叙述的化合物的原子意味着表示该原子的任何稳定同位素。 Unless otherwise specified, atom-containing compound described herein meant to represent any stable isotope of that atom. 举例来说,除非另有说明,否则当位置被特别地称为“H”或“氢”时,应了解该位置在其天然同位素组成中具有氢。 For example, unless otherwise stated, when a position is particularly referred to as "H" or "hydrogen", the position should be understood that have hydrogen at its natural isotopic composition.

[0082] “同位素富集”是指分子中特定原子上代替该原子的天然同位素丰度的特定同位素的量的掺入百分比。 [0082] "isotopically enriched" refers to the percentage of incorporation of an amount of a particular isotope in the molecule instead of the natural isotopic abundance of the atoms on a particular atom. 举例来说,特定位置上1%的氘富集意指特定样品中1%的分子在指定位置含有氘。 For example, 1% deuterium enrichment means that a particular location on a particular sample containing 1% of the molecules of deuterium at the specified position. 因为天然存在的氘分布是约0.0156%,所以使用非富集初始物质合成的化合物中任何位置的氘富集都是约〇. 〇156 %。 Because the naturally occurring distribution of deuterium is about 0.0156%, deuterium enrichment compound using non-enriched starting materials so synthesized are anywhere from about billion. 〇156%. 本文提供的化合物的同位素富集可以使用本领域的一般技术人员已知的常规分析法,包括质谱分析法和核磁共振谱法来测定。 The isotopic enrichment of the compounds provided herein may be used those of ordinary skill in the art of conventional analytical methods, including mass spectrometry and nuclear magnetic resonance spectroscopy is determined.

[0083] “同位素富集”是指原子具有除该原子的天然同位素组成以外的同位素组成。 [0083] "isotopically enriched" refers to an atom other than isotopes having a natural isotopic composition of that atom composition. “同位素富集”也可以指化合物含有至少一个具有除原子的天然同位素组成以外的同位素组成的原子。 "Isotopically enriched" may also refer to a compound containing at least one atom other isotopes of atoms other than the natural isotopic composition having a composition.

[0084] 如本文中所用,“烷基”、“烯基”、“炔基”、“环烷基”、“芳基”、“烷氧基”、“烷基羰氧基”、“芳氧基”、“烷氧基羰基”、“烷氧基烷基羰基”、“芳基烷氧基羰基”、“芳氧基羰基”、“烷氧基幾基烧基、“烧氧基幾基烧氧基、“烧基幾氧基烧基、“烧基—硫基烧基、“烧基幾基硫基烷基”、“芳基烷基”、“烷基芳基”、“羧基”、“羰基”、“杂芳基”、“杂芳基烷基”、“烷基杂芳基”和“氨基酸”基团任选地在一个或多个存在氢原子的位置上包含氘,并且其中原子的氘组成不是天然同位素组成。 [0084] As used herein, "alkyl", "alkenyl", "alkynyl", "cycloalkyl", "aryl", "alkoxy", "alkylcarbonyloxy", "aryl alkoxy "," alkoxycarbonyl "," alkoxyalkyl group "," aryl alkoxycarbonyl "," aryloxycarbonyl group "," alkoxy group burn several groups, "burn several group burning oxy group, "burn burn-yl oxy group several" burn-yl - thio group burn, "burn-ylthio group several alkyl", "arylalkyl", "alkylaryl", "carboxy "," carbonyl "," heteroaryl "," heteroarylalkyl "," alkylheteroaryl "and" amino acid "group is optionally in the presence of one or more hydrogen atoms on the positions containing deuterium, and wherein the deuterium composition of the atom is not a natural isotopic composition.

[0085] 如本文中所用,“烷基”、“烯基”、“炔基”、“环烷基”、“芳基”、“烷氧基”、“烷基羰氧基”、“芳氧基”、“烷氧基羰基”、“烷氧基烷基羰基”、“芳基烷氧基羰基,“芳氧基羰基”、“烧氧基幾基烧基、“烧氧基幾基烧氧基、“烧基幾氧基烧基“烧基—硫基烧基、“烧基幾基硫基烷基”、“芳基烷基”、“烷基芳基”、“羧基”、“羰基”、“杂芳基”、“杂芳基烷基”、“烷基杂芳基” 和“氨基酸”基团任选地包含非天然同位素组成的量的碳-13。 [0085] As used herein, "alkyl", "alkenyl", "alkynyl", "cycloalkyl", "aryl", "alkoxy", "alkylcarbonyloxy", "aryl alkoxy "," alkoxycarbonyl "," alkoxyalkyl group "," aryl alkoxycarbonyl, "aryloxycarbonyl group", "burn burn-yl group, several groups," burn-yl group several burn group, "burn burn-yl oxy group several" burn-yl - thio group burn, "burn-ylthio group several alkyl", "arylalkyl", "alkylaryl", "carboxy", "carbonyl", "heteroaryl", "heteroarylalkyl", "alkylheteroaryl" and "amino acid" groups optionally containing non-natural isotopic composition of an amount of carbon-13.

[0086] 如本文所用,EC5Q是指特定测试化合物引起的剂量依赖性反应是该特定测试化合物诱发、激起或增强的特定反应最大表现的50%时的剂量、浓度或量。 Dosage, concentration or amount of 50% of the maximum performance of the [0086] As used herein, EC5Q refers to a particular test compound that caused a dose-dependent response of the particular test compound is induced, provoked or enhanced specific reaction.

[0087] 如本文所用,术语“Emax”是指特定测试化合物在测量反应的测定中实现最大反应100 %抑制的量、浓度或剂量。 [0087] As used herein, the term "Emax" means that a particular test compound the amount of 100% inhibition of maximal response to a concentration in the assay or measurement reaction.

[0088] 如本文所用,IC5q是指特定测试化合物在测量反应的测定中实现最大反应50%抑制的量、浓度或剂量。 [0088] As used herein, IC5q refers to a particular test compound that achieves a 50% inhibition of the amount, concentration or dosage of the maximal response measured in the assay reaction.

[0089] 如本文所用,术语“宿主”是指任何单细胞或多细胞生物体,包括细胞系和动物,并且在某些实施方案中,指人。 [0089] As used herein, the term "host" refers to any unicellular or multicellular organism, including cell lines and animals, and in certain embodiments, a human. 可替代地,宿主可以运载复制或功能可以被本发明的化合物改变的黄病毒科(Flaviviridae)病毒基因组的一部分。 Alternatively a portion of, the host may carry replication or function can be altered according to the present invention is a compound of the Flaviviridae family (family Flaviviridae) of the viral genome. 术语宿主特别包括受感染细胞、被全部或一部分黄病毒科基因组转染的细胞和动物,尤其灵长类动物(包括黑猩猩)和人类。 The term host specifically includes infected cells, the transfected cells genome and animals, in particular, all or a portion of a primate flavivirus Albuquerque (including chimpanzees) and humans. 在本发明的大部分动物应用中,宿主是人类患者。 In most animal applications of the present invention, the host is a human patient. 但是,在某些适应症中,本发明清楚地预期兽医学应用(例如黑猩猩)。 However, in certain indications, the present invention clearly contemplated veterinary applications (such as chimpanzees).

[0090] 如本文所用,术语“受试者”和“患者”在本文中可互换使用。 [0090] As used herein, the terms "subject" and "patient" are used interchangeably herein. 术语“受试者”是指动物,例如哺乳动物,包括非灵长类动物(例如奶牛、猪、马、猫、犬、大鼠和小鼠)和灵长类动物(例如猴,例如食蟹猕猴、黑猩猩和人)和例如人。 The term "subject" refers to an animal, such as mammals, including non-primate (e.g. a cow, pig, horse, cat, dog, rat, and mouse) and a primate (e.g. a monkey, a cynomolgus e.g. monkeys, chimpanzees, and humans) for example, and people. 在另一实施方案中,受试者是农畜(例如马、奶牛、猪等)或宠物(例如犬或猫)。 In another embodiment, the subject is a farm animal (e.g. horse, cow, pig, etc.) or a pet (e.g., dog or cat). 在某些实施方案中,受试者是人。 In certain embodiments, the subject is a human.

[0091] 如本文所用,术语“治疗剂”是指可以用于治疗或预防病症或其一种或多种症状的任何药剂。 [0091] As used herein, the term "therapeutic agent" refers to treatment or prevention of a disorder or one or more symptoms of any agent. 在某些实施方案中,术语“治疗剂”包括本文提供的化合物。 In certain embodiments, the term "therapeutic agent" includes a compound provided herein. 在某些实施方案中, 治疗剂是已知可用于或已经或当前正用于治疗或预防病症或其一种或多种症状的药剂。 In certain embodiments, the therapeutic agent is known to be useful or been or currently being used for treating or preventing a disorder or one or more symptoms of the agent.

[0092] “治疗有效量”是指当化合物或组合物施用于受试者以治疗疾病时足够实现这类对疾病的治疗的量。 [0092] "therapeutically effective amount" refers to an amount of compound or composition administered to a subject for treating a disease is sufficient to effect such treatment for the disease. “治疗有效量”可以取决于尤其化合物、疾病和其严重度以及有待治疗的受试者的年龄、体重等而变化。 "Therapeutically effective amount" may be dependent on the age particular compound, the disease and its severity, and the subject to be treated, weight, etc., vary.

[0093]在某些实施方案中,任何疾病或病症的“治疗(treating或treatment)”是指改善受试者中存在的疾病或病症。 [0093] In certain embodiments, any disease or disorder "treatment (or treating, treatment)" refers to ameliorating the disease or disorder present in the subject. 在另一实施方案中,“治疗”包括改善受试者可能分辩不出的至少一个身体参数。 In another embodiment, "treating" include ameliorating at least one physical parameter of the subject may not differentiate. 在另一实施方案中,“治疗”包括在身体上(例如可辨别的症状的稳定) 或生理上(例如身体参数的稳定)或两方面调节疾病或病症。 In another embodiment, "treatment" includes two or modulating the disease or disorder in the body (e.g., stabilization of a discernible symptom) or physiologically (e.g., stabilization of a physical parameter). 在另一实施方案中,“治疗”包括延迟疾病或病症发作。 In another embodiment, "treatment" includes delaying the onset of a disease or disorder.

[0094] 如本文所用,如所用的术语“预防剂”是指可以用于预防病症或其一种或多种症状的任何药剂。 [0094] As used herein, as the term "prophylactic agent" refers to preventing a disorder or one or more symptoms of any agent. 在某些实施方案中,术语“预防剂”包括本文提供的化合物。 In certain embodiments, the term "prophylactic agent" includes compounds provided herein. 在某些其它实施方案中,术语“预防剂”不涉及本文提供的化合物。 In certain other embodiments, the term "prophylactic agent" does not relate to a compound provided herein. 举例来说,预防剂是已知可用于或已经或当前正用于预防或阻止病症发作、发展、进展和/或严重度的药剂。 For example, a prophylactic agent is known to be useful or has been or is currently being used to prevent or stop the onset of the disorder, development, pharmaceutical progress and / or severity.

[0095] 如本文所用,短语“预防有效量”是指疗法(例如预防剂)足以预防或减少与病症有关的一种或多种症状的发展、复发或发作或者足以增强或提高另一疗法(例如另一预防剂) 的预防作用的量。 [0095] As used herein, the phrase "prophylactically effective amount" refers to a therapy (e.g., prophylactic agent) sufficient to prevent or reduce the development of one or more symptoms associated with a disorder, recurrence or onset of or sufficient to enhance or improve another therapy ( another example preventative effect preventive agent).

[0096] 化合物 [0096] Compound

[0097] 本文提供了可用于治疗癌症,例如肝癌,例如肝细胞癌、胆管细胞型肝癌或胆道癌的核苷化合物。 [0097] Provided herein are useful for the treatment of cancer, such as liver cancer, for example hepatocellular carcinoma, cholangiocarcinoma nucleoside compounds or bile duct cancer. 所述核苷化合物可以如本文所述来形成并且用于治疗癌症,例如肝癌,例如肝细胞癌、胆管细胞型肝癌或胆道癌。 The nucleoside compounds may be formed as described herein and for the treatment of cancer, such as liver cancer, for example hepatocellular carcinoma, cholangiocarcinoma or bile duct cancer. 在某些实施方案中,癌症选自乳腺癌、卵巢癌、肺癌、 胰腺癌和白血病癌。 In certain embodiments, the cancer is selected from breast cancer, ovarian cancer, lung cancer, pancreatic cancer and leukemia.

[0098] 本文所述的化合物可以任选地呈药学上可接受的盐的形式使用。 [0098] The compounds described herein can optionally be in the form of a pharmaceutically acceptable salt. 应了解对化合物或其药用盐的提及将包括呈本发明形式以及呈不同形式的化合物,例如适合时多晶型物和溶剂化物(包括水合物)。 It should be understood to refer to a pharmaceutically acceptable salt thereof, or a compound of the present invention comprises, in the form of different forms as well as compounds of, for example, polymorphs and solvates (including hydrates).

[0099] 式I包括与5/-氨基磷酸酯基连接的手性氨基酸残基。 [0099] Formula I include 5 / - amino acid residues chiral phosphoramidate-linked. 本领域的技术人员将认识到氨基酸残基在与R4键结的碳处具有R立体化学;即,其是D-氨基酸残基。 Those skilled in the art will recognize that amino acid residue having R stereochemistry at the carbon bonded to R4; i.e., it is a D- amino acid residue.

[0100] 本文提供的一些化合物至少部分地是基于以下发现:D-氨基酸氨基磷酸酯前药可以提供优良的人类药物动力学,包括活性核苷和核苷酸类似物优先积累在例如肝细胞等靶细胞中。 [0100] Some of the compounds provided herein are at least in part on the discovery that: D- amino phosphoramidate prodrugs can provide superior kinetics in human medicine, including the activity of nucleoside and nucleotide analogues preferentially accumulate in the liver cells e.g. target cells. 在某些实施方案中,本文提供的化合物是D-氨基酸Rp氨基磷酸酯化合物。 In certain embodiments, the compounds provided herein are D- amino acids Rp phosphoramidate compound. 在某些实施方案中,本文提供的化合物是D-氨基酸Sp氨基磷酸酯化合物。 In certain embodiments, the compounds provided herein are D- amino acids Sp phosphoramidate compound. 本文提供的任何化合物优选地呈如本文所述,基本上不含化合物的其它立体异构体的组合物形式。 Any of the compounds provided herein preferably form as described herein, the composition is substantially free of other forms of stereoisomers of compounds.

[0101] 在一个实施方案中,本文所述的化合物是以下结构的化合物硫杂拉宾(thiarabine)的前药: [0101] In one embodiment, the compounds described herein is a compound of the following structure thia Rabin (thiarabine) prodrug:

[010; [010;

Figure CN108368147AD00151

[0103] 在一个实施方案中,R1与R2中的一个是氢并且另一个是 [0103] In one embodiment, R1 is and R2 is hydrogen and the other is a

[0104] [0104]

Figure CN108368147AD00152

[0105] 在一个实施方案中,R1和R2连同其连接的两个氧原子一起形成以下环结构: [0105] In one embodiment, R1 and R2 form a cyclic structure together with the two oxygen atoms connected to:

[0106] [0106]

Figure CN108368147AD00153

[0107]在一个实施方案中,是式II化合物: [0107] In one embodiment is a compound of formula II:

[01 Oi [01 Oi

Figure CN108368147AD00161

[0109] 条件是不包括下式化合物: [0109] with the proviso that a compound of the formula:

[0110] [0110]

Figure CN108368147AD00162

[0111] 其中R3是芳基或任选取代的杂芳基,R4是C1-K)烷基,1^是&-6烷基、C3-1Q环烷基、芳基C1-K)烷基或芳基,并且W是0或S。 [0111] wherein R3 is an optionally substituted aryl or heteroaryl, R4 is C1-K) alkyl, 1 ^ a & amp; -6 alkyl, C3-1Q cycloalkyl, aryl C1-K) alkoxy group or an aryl group, and W is 0 or S.

[0112] 在一个实施方案中,是式III化合物: [0112] In one embodiment, a compound of formula III:

[0113: [0113:

Figure CN108368147AD00163

[0114] 在一个实施方案中,是式IV化合物: [0114] In one embodiment, a compound of formula IV:

[0115] [0115]

Figure CN108368147AD00164

' η

[0116] 在一个实施方案中,是式V化合物: [0116] In one embodiment, a compound of formula V:

Figure CN108368147AD00171

O O

[0118]在一个实施方案中,R1与R2中的一个是氢并且另一个是 [0118] In one embodiment, R1 is and R2 is hydrogen and the other is a

Figure CN108368147AD00172

:或 :or

[0120] R1和R2连同其连接的两个氧原子一起形成以下环结构: I [0120] R1 and R2 together with the two oxygen atoms to which attached form a cyclic structure the following: I

Figure CN108368147AD00173

Figure CN108368147AD00174

[0122]在一个实施方案中,R1与R2中的一个是氢并且另一个是[C :或 [0122] In one embodiment, R1 is and R2 is a hydrogen and the other is [C: or

[0124] R1和R2连同其连接的两个氧原子一起形成以下环结构: [0124] R1 and R2 together with the two oxygen atoms connected to form the following ring structure:

Figure CN108368147AD00175

[0126]在一个实施方案中,R2是氢并且R1是 [0126] In one embodiment, R2 is hydrogen and R1 is

[0127] [0127]

Figure CN108368147AD00181

[0128] 在一个实施方案中,R1是氢并且R2是 [0128] In one embodiment, R1 is hydrogen and R2 is

[0129] [0129]

Figure CN108368147AD00182

[0130] 在一个实施方案中,R1和R2连同其连接的两个氧原子一起形成以下环结构。 [0130] In one embodiment, R1 and R2 together with the two oxygen atoms connected to form the following ring structure.

[0131] [0131]

Figure CN108368147AD00183

[0132] 在一个实施方案中,R4是氢或C1-Kj烷基,并且R5是C1-Kj烷氧基羰基或芳基。 [0132] In one embodiment, R4 is hydrogen or C1-Kj alkyl, and R5 is C1-Kj alkoxycarbonyl group or an aryl group.

[0133] 在一个实施方案中,R4是C1-K)烷基,并且R5是C1-K)烷基羰氧基C1-K)烷基。 [0133] In one embodiment, R4 is C1-K) alkyl, and R5 is C1-K) alkyl carbonyloxy C1-K) alkyl.

[0134] 在一个实施方案中,R4是氢,并且R5是芳基。 [0134] In one embodiment, R4 is hydrogen and R5 is aryl.

[0135] 在一个实施方案中,R4是氢、甲基或2-甲基丙基。 [0135] In one embodiment, R4 is hydrogen, methyl or 2-methylpropyl.

[0136] 在一个实施方案中,R5是C1-Kj烷氧基羰基、C1-Kj烷基羰氧基C1-Kj烷基或芳基。 [0136] In one embodiment, R5 is C1-Kj alkoxycarbonyl, C1-Kj alkylcarbonyloxy C1-Kj alkyl or aryl.

[0137] 在一个实施方案中,R5是C1-Kj烷基羰氧基C1-Kj烷基或芳基。 [0137] In one embodiment, R5 is C1-Kj alkylcarbonyloxy C1-Kj alkyl or aryl.

[0138] 在一个实施方案中,R5是C1-Kj烷基羰氧基C1-Kj烷基、C3-1Q环烷基羰氧基、芳基、芳氧基、C1-K)烷基芳基、芳基C1-K)烷基、杂芳基或杂芳基C1-K)烷基。 [0138] In one embodiment, R5 is C1-Kj alkylcarbonyloxy C1-Kj alkyl, C3-1Q cycloalkyl carbonyl group, aryl group, aryloxy group, C1-K) alkyl aryl , aryl C1-K) alkyl, heteroaryl or heteroaryl-C1-K) alkyl.

[0139] 在一个实施方案中,R5是甲氧基羰基、乙氧基羰基、异丙氧基羰基、甲基羰氧基甲基或苯基。 [0139] In one embodiment, R5 is a methoxycarbonyl group, an ethoxycarbonyl group, an isopropoxycarbonyl group, a carbonyl group, methyl or phenyl.

[0140] 在一个实施方案中,R5是甲基羰氧基甲基或苯基。 [0140] In one embodiment, R5 is methyl carbonyloxy methyl or phenyl.

[0141] 在一个实施方案中,R5是苯氧基羰基、苯甲氧基羰基和环戊基。 [0141] In one embodiment, R5 is a phenoxycarbonyl group, benzyloxycarbonyl group and cyclopentyl.

[0142] 在一个实施方案中,R3是氢、C1-K)烷氧基羰基C1-K)烷基、C1-K)烷基二硫基&-6烷基、 芳基或杂芳基C1-K)烷基,其中杂芳基经一个或两个选自C1-K)烷基和硝基的取代基取代。 [0142] In one embodiment, R3 is hydrogen, C1-K) alkoxy-carbonyl-C1-K) alkyl, C1-K) alkyl disulfide & amp; -6 alkyl, aryl or heteroaryl group C1-K) alkyl, wherein the heteroaryl group with one or two substituents selected from C1-K) alkyl and nitro substituents.

[0143] 在一个实施方案中,R3是C1-K)烷氧基羰基C1-K)烷基、C1-K)烷基二硫基&-6烷基、芳基或杂芳基C1-K)烷基,其中杂芳基经一个或两个选自C1-K)烷基和硝基的取代基取代。 [0143] In one embodiment, R3 is C1-K) alkoxy-carbonyl-C1-K) alkyl, C1-K) alkyl disulfide & amp; -6 alkyl, aryl or heteroaryl C1- K) alkyl, wherein the heteroaryl group with one or two substituents selected from C1-K) alkyl and nitro substituents.

[0144] 在一个实施方案中,R3不是芳基。 [0144] In one embodiment, R3 is not an aryl group.

[0145] 在一个实施方案中,R3是氢、甲氧基羰基甲基、乙氧基羰基甲基、(叔丁基二硫基) 乙基、苯基、(硝基呋喃基)甲基或(甲基硝基咪唑基)甲基。 [0145] In one embodiment, R3 is hydrogen, methoxycarbonyl methyl group, ethoxycarbonyl methyl group, (tert-butylthio) ethyl, phenyl, (nitro-furyl) methyl or (meth nitro-imidazolyl) methyl.

[0146] 在一个实施方案中,R3是氢、甲氧基羰基甲基、乙氧基羰基甲基、2-(叔丁基二硫基)乙基、苯基、(5-硝基-2-呋喃基)甲基或(3-甲基-2-硝基咪唑-4-基)甲基。 [0146] In one embodiment, R3 is hydrogen, methoxycarbonyl group, ethoxycarbonyl group, 2- (tert-butylthio) ethyl, phenyl, (5-nitro-2 - furyl) methyl or (3-methyl-2-nitro-imidazol-4-yl) methyl.

[0147] 在一个实施方案中,R3是杂芳基&-6烷基,其任选地经一个硝基取代。 [0147] In one embodiment, R3 is heteroaryl & amp; -6 alkyl, optionally substituted with a nitro group.

[0148] 在一个实施方案中,W是0。 [0148] In one embodiment, W is 0. 在另一实施方案中,W是S。 In another embodiment, W is S.

[0149] 在一个实施方案中,是式VI化合物: [0149] In one embodiment, a compound of formula VI:

[0150] [0150]

Figure CN108368147AD00191

7 7

[0151] 其中R5是Cl-IQ烧基幾氧基Cl-IQ烧基、C3-1Q环烧基幾氧基、芳基、芳氧基、Cl-IQ烧基芳基、芳基C1-K)烷基、杂芳基或杂芳基C1-K)烷基。 [0151] wherein R5 is Cl-IQ group burn burn Cl-IQ several yloxy group, C3-1Q cycloalkyl group fired several groups, aryl groups, aryloxy, Cl-IQ burn aryl, aryl-C1-K ) alkyl, heteroaryl or heteroaryl-C1-K) alkyl.

[0152] 在一个实施方案中,是式VII化合物: [0152] In one embodiment is a compound of formula VII:

[0153; [0153;

Figure CN108368147AD00192

[0154] 其中R5是Cl-IQ烧氧基幾基、C3-1Q环烧氧基幾基、Cl-IQ烧基幾氧基Cl-IQ烧基、C3-1Q环烧基幾氧基、芳基、芳氧基、Ci-io烧基芳基、芳基Ci-io烧基、芳基Ci-io烧氧基幾基、芳氧基幾基、 杂芳基或杂芳基C1-K)烷基。 [0154] wherein R5 is Cl-IQ group burning several groups, C3-1Q cycloalkyl group fired several groups, Cl-IQ group burn burn Cl-IQ several yloxy group, C3-1Q cycloalkyl group fired several groups, aryl group, aryloxy group, Ci-io aryl burn, burn Ci-io aryl, aryl Ci-io alkoxy several burning, aryloxy several groups, heteroaryl or heteroaryl-C1-K) alkyl.

[0155] 在一个实施方案中,是式VIII化合物: [0155] In one embodiment, a compound of formula VIII:

[0156] [0156]

Figure CN108368147AD00201

[0157] 其中R是C1-K)烷基。 [0157] wherein R is a C1-K) alkyl.

[0158] 在一个实施方案中,R是异丙基。 [0158] In one embodiment, R is isopropyl.

[0159] 在一个实施方案中: [0159] In one embodiment:

[0160] R1是 [0160] R1 is

Figure CN108368147AD00202

[0161] R2 是氢, [0161] R2 is hydrogen,

[0162] R3是杂芳基C1-!。 [0162] R3 is heteroaryl C1- !. 烷基; alkyl;

[0163] R4是氣; [0163] R4 is a gas;

[0164] R5是芳基;并且 [0164] R5 is an aryl group; and

[0165] W是〇。 [0165] W is square.

[0166] 以上每个实施方案中的所有其它变量如式1、11、111、1¥、¥、¥1,11和¥111每个式以及其它实施方案中所定义。 [0166] all other variables are each of the above embodiments of Formula 1,11,111,1 ¥, ¥, ¥ 1,11 ¥ 111, and each of the other embodiments of formula and defined.

[0167] 在某些实施方案中,本文提供了根据任一下式的化合物: [0167] In certain embodiments, the compounds provided herein according to any of formulas:

Figure CN108368147AD00211

Figure CN108368147AD00221

[0170; [0170;

Figure CN108368147AD00231

[0171] 和其药学上可接受的盐。 [0171] and pharmaceutically acceptable salts thereof.

[0172] 特定化合物是: [0172] Specific compounds are:

[0173] [0173]

Figure CN108368147AD00232

[0174] [0174]

Figure CN108368147AD00241

[0175] 和其药学上可接受的盐。 [0175] and pharmaceutically acceptable salts thereof.

[0176] 在一些实施方案中,本文提供了: [0176] In some embodiments, it provided herein:

[0177] (a)如本文所述的例如式I-VIII的化合物,或其药学上可接受的盐和组合物; [0177] (a) a compound of formula I-VIII, for example, as described herein, or a pharmaceutically acceptable salt thereof, and combinations thereof;

[0178] ⑹如本文所述的例如式I-VIII的化合物,或其药学上可接受的盐和组合物,其用于治疗中; [0178] ⑹ e.g. compound of formula I-VIII as described herein, or pharmaceutically acceptable salts and compositions thereof, for use in therapy;

[0179] (c)如本文所述的例如式I-VIII的化合物,或其药学上可接受的盐和组合物,其用于治疗和/或预防癌症,例如肝癌、乳腺癌、卵巢癌、肺癌、胰腺癌或白血病癌; [0179] (c) a compound as described herein, for example, of formula I-VIII, or a pharmaceutically acceptable salt thereof and compositions for the treatment and / or prevention of cancer, such as liver cancer, breast cancer, ovarian cancer, lung cancer, pancreatic cancer or leukemia;

[0180] (d)用于制备如本文所述的例如式I-VIII的化合物的方法,如本文中其它地方更详细地描述; [0180] (d) the method for producing compound I-VIII, for example of the type described herein, as described elsewhere herein in more detail;

[0181] (e)包含如本文所述的例如式I-VIII的化合物或其药学上可接受的盐以及药学上可接受的载体或稀释剂的药物组合物; [0181] (e) comprises, as described herein, for example, a compound of formula I-VIII or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent of the pharmaceutical composition;

[0182] (f)包含任选地在药学上可接受的载体或稀释剂中的如本文所述的例如式I-VIII 的化合物或其药学上可接受的盐以及一种或多种其它有效治疗剂,例如抗癌剂的药物制剂; [0182] (f) optionally comprising in a pharmaceutically acceptable carrier or diluent, such as, for example, a compound of formula I-VIII, or a pharmaceutically acceptable salt thereof as described herein, and one or more other active therapeutic agent, such a pharmaceutical formulation of an anticancer agent;

[0183] (g)治疗和/或预防患有癌症,例如肝癌、乳腺癌、卵巢癌、肺癌、胰腺癌或白血病癌的宿主的方法,其包括施用有效量的如本文所述的例如式I-VIII的化合物、其药学上可接受的盐或组合物; [0183] (g) and or, such as liver cancer, breast cancer, ovarian cancer, lung cancer, pancreatic cancer or leukemia method host cancer / prevention of cancer therapy, which comprises administering an effective amount of a Formula I described herein, e.g. -VIII the compound, pharmaceutically acceptable salt or composition thereof;

[0184] ⑹治疗和/或预防患有癌症,例如肝癌、乳腺癌、卵巢癌、肺癌、胰腺癌或白血病癌的宿主的方法,其包括施用有效量的如本文所述的例如式I-VIII的化合物、其药学上可接受的盐或组合物,与其它有效治疗剂,例如抗癌剂组合和/或交替;或 [0184] ⑹ and / or prevention of cancer, such as liver cancer, breast cancer, ovarian cancer, lung cancer, a method of treating a host of pancreatic cancer or leukemia, comprising administering an effective amount of a formula as described herein, for example, I-VIII the compound, pharmaceutically acceptable salt or composition thereof, effective with other therapeutic agents, for example, anticancer agents and / or alternating; or

[0185] (i)包含如本文所述的例如式I-VIII的化合物或药学上可接受的盐以及一种、两种、三种或更多种其它治疗剂,例如抗癌剂的组合; [0185] (i) comprises, as described herein, for example, a compound of formula I-VIII or a pharmaceutically acceptable salt thereof and one, two, three or more other therapeutic agents, such as a combination of the anticancer agent;

[0186] 光学活性化合物 [0186] optically active compound

[0187] 应了解本文提供的化合物具有若干手性中心,并且可以呈光学活性和外消旋形式存在和分离。 [0187] should be understood that the compounds provided herein have several chiral centers and may exist as a separate and optically active and racemic forms. 一些化合物可以展现多晶型。 Some compounds may exhibit polymorphism. 应了解具有本文所述的有用性质的本文提供的化合物的任何外消旋、光学活性、非对映异构体、多晶型或立体异构体形式或其混合物都在本发明的范围内。 Should be understood that any racemic having useful properties described herein, a compound provided herein, optically active, diastereomers thereof, polymorphs or stereoisomeric form, or mixtures thereof are within the scope of the invention. 本领域中众所周知如何制备光学活性形式(例如通过再结晶技术拆分外消旋形式,通过由光学活性起始物质合成,通过手性合成或通过使用手性固定相进行色谱分尚)。 It is known in the art how to prepare optically active forms (for example by recrystallization from technical resolution of racemic forms, by synthesis from the optically active starting materials, by chiral synthesis, or by partial still using a chiral stationary phase chromatography).

[0188] 本文所述的化合物,即式I-VIII中任一式的化合物,可以具有一个或多个手性(不对称)中心。 [0188] The compounds described herein, a compound of formula, i.e. of formula I-VIII any, may have one or more chiral (asymmetric) centers. 本公开涵盖本文所述的化合物的所有立体异构体形式。 All stereoisomeric forms of the compounds disclosed herein encompasses the present. 存在于本文所述的化合物中的不对称中心可以彼此独立地具有⑻或⑸构型。 Present in the compounds described herein are asymmetric centers may independently of each other or ⑻ ⑸ configuration. 当在本文所述的化合物的结构式中将与例如碳或磷等手性原子键结的键描绘成直线时或当在手性原子未指定0?)或(S)手性下叙述化合物名称时,应了解每个这种手性原子的0?)和⑸构型和因此每种对映异构体或非对映异构体和其混合物都涵盖在结构式或名称内。 When in the compound of formula described herein and the like such as a key or a phosphorus chiral carbon atom bonded to depict a straight line or when the unspecified chiral atom 0?) Or (S) chiral compound names described , 0 should be understood that each of these chiral atom?) and ⑸ configuration and therefore each of the enantiomers or diastereomers and mixtures thereof are encompassed within the structural formula or name. 特定立体异构体或其混合物的产生可以在获得此类立体异构体或混合物的实施例中进行鉴别,但这决不限制所有立体异构体和其混合物包括在本公开的范围内。 Generate a specific stereoisomer or a mixture thereof can be identified is obtained in such stereoisomers or mixtures embodiments, but in no way limit all stereoisomers and mixtures thereof are included within the scope of the present disclosure.

[0189] 因为核苷的r和V碳是手性的,所以其非氢取代基(分别是碱基和CHOR基团)相对于糖环系统可以是顺式(在同侧上)或者反式(在对侧上)。 [0189] Since r and V nucleosides are chiral carbon, so the non-hydrogen substituent (respectively CHOR groups and bases) with respect to the sugar ring system may be of formula cis (on the same side) or trans (on the opposite side). 因此,四种光学异构体由以下构型表示(此时糖部分在水平面上取向,使得氧原子在背面):顺式(两个基团“向上”,对应于天然存在的β-D核苷的构型)、顺式(两个基团“向下”,这是非天然存在的β-L构型)、反式(C2/取代基“向上”,并且Cf取代基“向下”)和反式(C2/取代基“向下”,并且Cf取代基“向上”),D_核苷”是呈天然构型的顺式核苷,并且“L-核苷”是呈非天然存在的构型的顺式核苷。 Thus, four kinds of optical isomers represented by the following configurations (when oriented sugar moiety in a horizontal plane, so that the oxygen atom at the back): cis (two groups "up", corresponding to β-D nuclear naturally occurring configuration), cis (glycoside two groups "down", which is a non-naturally occurring β-L configuration), "up" trans (C2 / substituent group, and Cf substituent "down") and non-naturally occurring trans (C2 / substituent "down" and Cf substituent "up"), D_ nucleoside "natural configuration is in the form of cis-nucleosides, and" L-nucleoside "is in the form configuration cis nucleosides.

[0190] 同样,大部分氨基酸是手性的(指定为L或D,其中L对映异构体是天然存在的构型) 并且可以呈分开的对映异构体存在。 [0190] Likewise, most amino acids are chiral (designated as L or D, wherein the L enantiomer is the naturally occurring configuration) and can form separate enantiomers exist.

[0191] 获得光学活性物质的方法的实例是本领域中已知的,并且包括至少以下方法。 Examples [0191] The method of obtaining optically active substances is known in the art, and include at least the following method.

[0192] i)结晶的物理分离-一项将个别的对映异构体的肉眼可见的结晶人工分开的技术。 Physical separation [0192] i) crystalline - a crystallization of the individual enantiomers separated Artificial macroscopic technique. 如果存在分开的对映异构体的结晶,即物质是团块并且在视觉上结晶是不同的,那么可以使用这项技术; If there are separate crystalline enantiomers, i.e. the material is crystallized agglomerates and are visually different, then this technique may be used;

[0193] ii)同时结晶-一项使个别的对映异构体分别从外消旋体溶液中结晶的技术,可能只有在后者是呈固态的团块时; [0193] ii) simultaneous crystallization - a make individual enantiomers are crystallized from a solution of racemic technology, which may be in solid agglomerate form when;

[0194] iii)酶法拆分-一项根据对映异构体在酶下不同的反应速率而部分或完全分离外消旋体的技术; [0194] iii) enzymatic resolutions - a technique according to different enantiomers of reaction rate in the partial or complete separation of a racemate enzyme;

[0195] iv)酶法不对称合成-一项合成技术,其中至少一个合成步骤使用酶促反应来获得所需对映异构体的对映异构体纯或富集的合成前体; [0195] iv) enzymatic asymmetric synthesis - a synthetic technique, wherein the at least one synthesis step enzymatic reaction using synthetic precursor to obtain enantiomerically pure or enriched in the desired enantiomer;

[0196] V)化学不对称合成-一项合成技术,其由非手性前体,在产物中产生不对称(即手性)的条件下合成所需对映异构体,不对称(即手性)的产生可以使用手性催化剂或手性助剂来实现; [0196] V) chemical asymmetric synthesis - a synthesis of the desired synthesis under conditions that produce asymmetry (i.e., chirality) by a front body achiral product enantiomer, asymmetric (i.e. chiral) can be produced using chiral catalysts or chiral auxiliaries to achieve;

[0197] vi)非对映异构体分离-一项使外消旋化合物与将个别对映异构体转变成非对映异构体的对映异构体纯的试剂(手性助剂)起反应的技术。 [0197] vi) diastereomer separation - a racemic compound and the individual (the chiral auxiliary enantiomerically pure reagent into enantiomers diastereomers body ) from technical reaction. 接着所得到的非对映异构体通过色谱法或结晶,根据其现在更不同的结构差异来分离,并且随后去除手性助剂,从而获得所需对映异构体; Then the resulting diastereomers by chromatography or crystallization, separated according to their structural differences more different now, and then removing the chiral auxiliary to obtain the desired enantiomer;

[0198] vi i)—级和二级不对称转换-一项使来自外消旋体的非对映异构体平衡以使非对映异构体在溶液中相对于所需对映异构体具有优势,或者非对映异构体相对于所需对映异构体的优先结晶扰乱了这种平衡,以至于最终在原则上所有物质都从所需对映异构体转变成结晶非对映异构体的技术。 [0198] vi i) - conversion stage and two asymmetric - a non enantiomers from racemates balanced so diastereomers relative to desired enantiomer in solution has advantages, or diastereomer thereof for the preferential crystallization of the desired enantiomer disrupt this balance, so that eventually in principle all substances enantiomers required to change from non-crystalline technology enantiomers. 接着从非对映异构体释放所需对映异构体; Then the diastereomers thereof liberate the desired enantiomer;

[0199] viii)动力学拆分-这项技术是指根据在动力条件下对映异构体与手性非外消旋试剂或催化剂的不相等的反应速率,实现外消旋体的部分或完全拆分(或部分拆分的化合物的进一步拆分); [0199] viii) kinetic resolution - this technique refers to the power under the conditions according to unequal reaction rates of the enantiomers with a chiral, non-racemic reagent or catalyst to achieve some or racemate completely split (split or further partially resolved compound);

[0200] ix)由非外消旋前体进行对映特异性合成-一项合成技术,其中由非手性起始物质获得所需对映异构体并且其中在合成过程中立体化学完整性未受损或仅仅最低限度地受损; [0200] ix) by non-racemic precursors enantiomer specific synthesis - a synthetic technique, which is obtained wherein the stereochemical integrity and desired enantiomer in the synthesis of a non-chiral starting materials undamaged or minimally damaged only;

[0201] X)手性液相色谱法-一项在液体流动相中根据与固定相的不同相互作用分离外消旋体的对映异构体的技术。 [0201] X) chiral liquid chromatography - a technique phase enantiomers racemates is separated according to the different interaction of the stationary phase in a liquid flow. 固定相可以用手性物质制成或流动相可以含有额外的手性物质以激起不同相互作用; Stationary phase can be made of chiral material or the mobile phase can contain an additional chiral material to provoke the differing interactions;

[0202] xi)手性气相色谱法-一项将外消旋体蒸发并利用含有固定的非外消旋手性吸附相的柱根据在气体流动相中的不同相互作用将对映异构体分离的技术; [0202] xi) chiral gas chromatography - a racemate was evaporated and the column using non-racemic chiral adsorbent phase containing immobilized depending on the interaction of the gas phase flow enantiomers separation techniques;

[0203] xii)用手性溶剂萃取-一项根据一种对映异构体优先溶解到特定手性溶剂中而分离对映异构体的技术; [0203] xii) extraction with chiral solvents - a technique to separate the enantiomers according to a particular chiral solvent preferentially one enantiomer was dissolved in;

[0204] a)跨过手性膜传送-一项使外消旋体与薄膜屏障接触的技术。 [0204] a) transmitted across chiral membranes - a technique that the racemate contact with a thin membrane barrier. 屏障典型地分离两种混溶流体,一种流体含有外消旋体,并且例如浓度或压差等驱动力引起优先跨越膜屏障的传送。 Typically the barrier separation of the two immiscible fluids, one fluid containing the racemate, and the like, for example, the concentration or pressure differential causes the driving force across the membrane barrier transport priority. 分离是由膜的非外消旋手性引起的,这允许仅仅通过外消旋体的一种对映异构体。 Separated by chiral nonracemic film caused, which allows only by means of a racemate of enantiomers.

[0205] 在一些实施方案中,提供了一种包含本文所述的化合物的基本上纯的指定对映异构体的组合物。 [0205] In some embodiments, a substantially pure composition specified herein, comprising a compound of the enantiomers. 在某些实施方案中,在本发明的方法和化合物中,化合物基本上不含其它对映异构体。 In certain embodiments, the methods and compounds of the present invention, the compound is substantially free of other enantiomers. 在一些实施方案中,组合物包括占化合物的至少85重量%、90重量%、95重量%、 98重量%、99重量%或100重量%的化合物,其余包含其它化学物质或对映异构体。 In some embodiments, the composition comprising the compound comprises at least 85 wt%, 90 wt%, 95 wt%, 98 wt%, 100%, or 99 wt% of the weight of the compound, the remainder comprising other chemical species or enantiomers .

[0206] 在一个实施方案中,对映异构体是呈对映异构体纯形式、呈左旋和右旋对映体、呈外消旋体形式和呈两种对映异构体以所有比率的混合物形式的本发明主题。 [0206] In one embodiment, the enantiomer is in the form of the enantiomerically pure form, L form and as dextrorotatory antipodes, racemic forms and placed in two enantiomers in all a mixture ratio relating to the present invention. 在顺式/反式异构的情况下,本发明包括顺式与反式以及这些形式以所有比率的混合物。 In the cis / trans isomerism, the present invention includes cis and trans, and mixtures of these forms in all ratios. 必要时,个别立体异构体的制备可以通过利用惯常方法,例如通过色谱法或结晶分离混合物,通过使用立体化学均匀的起始物质进行合成或进行立体选择性合成来进行。 If necessary, the preparation of individual stereoisomers can be prepared by using a conventional method, such as a mixture separated by chromatography or crystallization, synthesized by the use of stereochemically uniform starting materials or stereoselective synthesis is performed. 任选地,衍生化可以在分离立体异构体前进行。 Optionally, a derivatization can be carried out before separation of stereoisomers. 立体异构体混合物的分离可以在本文所述的化合物,例如式I-VIII 中任一式的化合物合成期间在中间步骤进行,或者其可以在最终外消旋产物上进行。 Separating a mixture of stereoisomers may be, for example, any of Formula I-VIII during the synthesis of a compound of formula in an intermediate step in the compounds described herein, or it may be performed on the final racemic product. 绝对立体化学可以通过结晶产物或结晶中间体的X射线晶体学确定,必要时,结晶产物或结晶中间体用含有已知构型的立体异构中心的试剂衍生化。 Absolute stereochemistry may be determined by the crystalline products or crystalline intermediates X-ray crystallography, if necessary, the crystalline products or crystalline intermediates with a reagent containing a known configuration of stereogenic centers derivatized. 可替代地,绝对立体化学可以通过振动圆二色性(Vibrational Circular Dichroism,VCD)光谱分析来确定。 Alternatively, the absolute stereochemistry may be determined by vibrational circular dichroism (Vibrational Circular Dichroism, VCD) Spectroscopy. 本发明包括所有这类的异构体以及这类外消旋体、对映异构体、非对映异构体和互变异构体的盐、溶剂化物(其包括水合物)和溶剂化盐以及其混合物。 The present invention includes all such isomers and such racemates, enantiomers, diastereomers and salts, solvates (including hydrates) of tautomers and solvates salts thereof and mixtures thereof.

[0207] 同位素富集的化合物 [0207] isotopically enriched compound

[0208] 本文还提供了同位素富集的化合物,包括但不限于同位素富集的5/-D-氨基酸氨基磷酸酯化合物。 [0208] Also provided herein are isotopically enriched compounds, including, but not limited to, 5 / -D- amino phosphoramidate isotopically enriched compound.

[0209] 先前已经用一些类别药物证明了药物的同位素富集(例如氘化)改善药物动力学(“PK”)、药效学(“PD”)和毒性特征。 [0209] Some classes of drugs have been previously demonstrated using isotopically enriched drug (e.g., deuterated) improved pharmacokinetic ( "PK"), pharmacodynamics ( "PD") and toxicity characteristics. 参见例如Lijinsky等人,Food Cosmet.Toxicol.,20: 393 (1982) ;Lijinsky等人,J.Nat.Cancer Inst.,69:1127 (1982) ;Mangold等人,Mutation Re s.308:33 (1994) ; Go rdon 等人,Drug Me tab .Dispos.,15:589 (1987) ;Zello 等人, Metabo Ii sm,43 :487 (1994) ; Gate Iy 等人,J .Nuc I .Med.,27 :388 (1986) ; Wade D, Chem.Biol·Interact.117:191 (1999)〇 See, for example, Lijinsky et al., Food Cosmet.Toxicol, 20: 393 (1982); Lijinsky et al., J.Nat.Cancer Inst, 69:. 1127 (1982); Mangold et al, Mutation Re s.308:. 33 ( 1994); Go rdon et al., Drug Me tab .Dispos, 15: 589 (1987); zello et al., Metabo Ii sm, 43:. 487 (1994); Gate Iy et al., J .Nuc I .Med,. 27: 388 (1986); Wade D, Chem.Biol · Interact.117: 191 (1999) square

[0210]药物的同位素富集可以用于例如⑴减少或消除不需要的代谢物;⑵增加母体药物的半衰期;(3)减少实现预期作用所需的给药次数;(4)减少实现预期作用所需的剂量; (5)增加活性代谢物的形成(如果形成的话);和/或(6)减少特定组织中有害代谢物的产生和/或创造更有效的药物和/或更安全的药物以供组合疗法用,无论组合疗法是有意还是无O [0210] isotopically enriched drug may, for example, to reduce or eliminate unwanted ⑴ metabolites; ⑵ increase the half-life of the parent drug; (3) reduce the number of doses required to achieve the desired effect; (4) reduction to achieve the desired effect dose required; (5) increase the formation of active metabolites (if formed); and / or (6) reduction in specific tissues produce harmful metabolites and / or create a more effective drug and / or safer drug for use in combination therapy, whether the combination therapy is intentional or not O

[0211] 原子被置换成其同位素之一经常引起化学反应的反应速率改变。 [0211] atom is replaced into one of its isotopes often causes the reaction rate of a chemical reaction change. 这种现象被称为动力学同位素效应(Kinetic Isotope Effect,“KIE”)。 This phenomenon is called kinetic isotope effect (Kinetic Isotope Effect, "KIE"). 举例来说,如果CH键在化学反应中的速率决定步骤(即具有最高过渡状态能量的步骤)期间断裂,那么氘取代该氢将引起反应速率下降并且该过程将减慢。 For example, if a CH bond in the rate determining step in a chemical reaction (i.e. the step with the highest transition state energy) during a break, then the hydrogen will cause a deuterium substitution reaction rate decreases and the process will slow down. 这种现象被称为氖动力学同位素效应(Deuterium Kinetic Isotope Effect,“DKIE”)(参见例如Foster 等人,Adv.Drug Res·,第14 卷,第1-36 页(1985) ;Kushner等人,Can. J.Physiol .Pharmacol ·,第77卷,第79-88页(1999)) 〇 This phenomenon is known as neon kinetic isotope effects (Deuterium Kinetic Isotope Effect, "DKIE") (see Foster et al, Adv.Drug Res ·, Vol. 14, pp. 1-36 (1985) for example; Kushner et al. , Can. J.Physiol .Pharmacol ·, Vol. 77, pp. 79-88 (1999)) billion

[0212] DKIE的程度可以表示为其中CH键断裂的特定反应的速率与氘取代氢的相同反应的速率之间的比率。 [0212] degree DKIE can be expressed as the ratio between the CH bond is broken, wherein the rate of substitution of deuterium for a particular reaction rate of the same reaction of hydrogen. DKIE可以在约1 (无同位素效应)至极大数目,例如50或更多数目的范围内,意味着当氘取代氢时反应可以减慢五十倍或更多倍。 DKIE can (no isotope effect) to very large number of approximately 1, for example, in the range of 50 or more numbers, means that when deuterium is substituted for hydrogen the reaction can be slowed down five times or more. 高DKIE值可能部分归因于被称为穿隧的现象,穿隧是不确定性原理的结果。 DKIE high value may be partly due to the phenomenon known as tunneling, tunneling is the result of the uncertainty principle. 穿隧被归于氢原子的质量小,并且是因为涉及质子的过渡状态有时可以在缺乏所需活化能下形成而发生。 Small tunneling quality has been attributed to a hydrogen atom, and because the transition state involving a proton can sometimes occur in the absence of the required activation energy is formed. 因为氘的质量比氢大,所以在统计学上其经历这种现象的概率要低得多。 Because the probability is greater than the mass of deuterium hydrogen, so statistically it experienced this phenomenon is much lower.

[0213] 氚(“T”)是氢的一种放射性同位素,用于研究、聚变反应堆、中子发生器和放射性药物中。 [0213] Tritium ( "T") is a radioactive isotope of hydrogen, used in research, fusion reactors, neutron generators and radiopharmaceuticals. 氚是原子核中具有2个中子并且原子量接近3的氢原子。 Tritium is a nucleus having two neutrons and an atomic weight close to 3 hydrogen atom. 其在环境中天然存在,浓度极低,最常发现其呈T20。 Its natural presence in the environment at very low concentrations, most commonly found in a T20. 氚衰变缓慢(半衰期=12.3年),并且发射无法穿透人类皮肤外层的低能量β粒子。 Tritium decays slowly (half-life = 12.3 years) and emits a low energy β particles can not penetrate the outer layer of human skin. 体内照射是与此同位素有关的主要危险,然而,造成显著的健康风险,必须大量摄取其。 Irradiation in vivo is a major risk associated with this isotope, however, cause significant health risk, it must be ingested in large amounts. 同氘比较,氚要到达危险水平,须消耗的量较少。 Compare with deuterium, tritium to reach dangerous levels, a smaller amount to be consumed. 氚(“Τ”)取代氢产生比氘更强的键,并且产生数值上更大的同位素效应。 Tritium ( "Τ") substituted with deuterium for hydrogen generation stronger than bonds and a greater value of the isotope effect. 类似地,其它元素的同位素取代,包括(但不限于)碳的13C或14C、硫的33S、34S或36S、氮的15N和氧的17O或180,可以产生类似的动力学同位素效应。 Similarly, isotopes of other elements substituents, including (but not limited to) carbon. 14C or 13C, sulfur 33S, 34S or 36S, nitrogen and oxygen 15N 17O or 180, can produce a similar kinetic isotope effect.

[0214] 举例来说,据推测,DKIE通过限制例如三氟乙酰氯等活性物质,用于减少海罗芬的肝脏毒性。 [0214] For example, presumably, by limiting The DKIE e.g. trifluoroacetyl chloride and other active substances, for reducing the hepatotoxicity Hai Luofen. 但是,这种方法可能不适于所有药物类别。 However, this approach may not be suitable for all drug classes. 举例来说,氘掺入可以引起代谢转换。 For example, deuterium incorporation can lead to metabolic switching. 代谢转换的概念说明当被I相酶螯合时xenogen可以在化学反应(例如氧化)前以多种构象短暂地结合和再结合。 Concept of metabolic switching instructions when chelating xenogen Phase I enzymes may bind transiently and re-bind in front of a chemical reaction (e.g., oxidation) in a variety of conformations. 此假设由以下支持:许多I相酶中结合袋的尺寸相对巨大,以及许多代谢反应的混杂性。 This support is assumed by the following: many Phase I enzymes and the binding pocket size is relatively large, and promiscuity many metabolic reactions. 代谢转换可以产生不同比例的已知代谢物以及完全新的代谢物。 Metabolic switching can produce different proportions of known metabolites as well as altogether new metabolites. 此新的代谢特征可能带来或多或少的毒性。 This new metabolic profile may bring more or less toxicity.

[0215] 动物体表达多种酶,以将例如治疗剂等外来物质从其循环系统消除。 [0215] Expression of various enzymes animal body, such as a therapeutic agent to a foreign substance from the circulation system to eliminate. 此类酶的实例包括细胞色素P450酶(“CYP”)、酯酶、蛋白酶、还原酶、脱氢酶和单胺氧化酶,这些酶与这些外来物质反应并将这些外来物质转变成极性更大的中间体或代谢物以进行肾排泄。 Examples of such enzymes include the cytochrome P450 enzymes ( "CYP"), esterases, proteases, reductases, dehydrogenases, and monoamine oxidase enzymes that react with these foreign substances and convert these foreign substances to more polar intermediate or metabolites for renal excretion. 药物化合物的一些最常见的代谢反应涉及碳-氢(CH)键氧化成碳-氧(CO)或者碳-碳(CC) π 键。 Some of the most common metabolic reactions of pharmaceutical compounds involve the carbon - hydrogen (CH) bonds oxidized into carbon - oxygen (CO) or a carbon - carbon (CC) π bond. 所得到的代谢物在生理条件下可能稳定或不稳定,并且可以具有相对于母体化合物,基本上不同的药物动力学、药效学以及急性和慢性毒性特征。 The resultant metabolites may be stable or unstable under physiological conditions and may have relative to the parent compound, substantially different pharmacokinetic, pharmacodynamic, and acute and chronic toxicity characteristics. 对于许多药物来说,此类氧化是迅速的。 For many drugs, such oxidation is rapid. 因此,这些药物经常需要施用多个或高的日剂量。 Thus, administration of these drugs often require multiple or high daily doses.

[0216] 因此,在本文提供的化合物的某些位置的同位素富集将产生可检测的KTE,与具有天然同位素组成的类似化合物相比,此将影响本文提供的化合物的药物动力学、药理学和/ 或毒物学特征。 [0216] Therefore, isotopic enrichment at certain positions of a compound provided herein will produce a detectable KTE, compared to a similar compound having a natural isotopic composition, this will affect the drug compound provided herein kinetics, pharmacology and / or toxicological characteristics.

[0217] 化合物的制备 Preparation of [0217] compound

[0218] 本文提供的化合物可以通过本领域的技术人员显而易见的任何方法来制备、分离或获得。 [0218] The compounds provided herein can be by any method apparent to those skilled in the art to be prepared, isolated or obtained. 本文提供的化合物可以根据以下提供的示例性制备方案来制备。 The compounds provided herein may be prepared according to the exemplary embodiment provided below was prepared. 示例性制备方案中未提供的反应条件、步骤和反应物将是本领域的技术人员显而易见并且已知的。 The reaction conditions for the preparation of an exemplary embodiment is not provided, and the step of reactants will be apparent to those skilled in the art and known.

[0219] 示例性制备方案 [0219] An exemplary embodiment Preparation

[0220] 方案A [0220] Scheme A

[0221] [0221]

Figure CN108368147AD00281

[0222] 方案B [0222] Scheme B

[0223] [0223]

Figure CN108368147AD00282

[0224] 其中R1和R2之一是氢,并且P是保护基,例如dMTr [0224] wherein one of R1 and R2 is hydrogen, and P is a protecting group, e.g. dMTr

[0225] 方案C [0225] Scheme C

[0226] [0226]

Figure CN108368147AD00291

[0227] 其中R1和R2之一是氢,并且P是保护基,例如dMTr [0227] wherein one of R1 and R2 is hydrogen, and P is a protecting group, e.g. dMTr

[0228] 方案D [0228] Scheme D

[0229] [0229]

Figure CN108368147AD00292

[0230] 在示例性制备方案中,变量如式I至IV的情况下所述。 [0230] In an exemplary preparation scheme, the variables are as formula I to IV in the case. 核苷可以根据本领域中的知识来制备或获得。 Nucleosides can be obtained or prepared according to the knowledge in the art. 本领域的技术人员将知道示例性制备方案中未提供的额外步骤和试剂。 Those skilled in the art will appreciate that additional steps and reagents exemplary embodiment are not provided was prepared. 示例性制备方法详细描述于本文中的实施例中。 Exemplary methods of preparation are described in detail in the embodiments herein.

[0231] 在示例性制备方案中,变量如式I至IV的情况下所述。 [0231] In an exemplary preparation scheme, the variables are as formula I to IV in the case. 核苷可以根据本领域中的知识来制备或获得。 Nucleosides can be obtained or prepared according to the knowledge in the art. 本领域的技术人员将知道示例性制备方案中未提供的额外步骤和试剂。 Those skilled in the art will appreciate that additional steps and reagents exemplary embodiment are not provided was prepared. 示例性制备方法详细描述于本文中的实施例中。 Exemplary methods of preparation are described in detail in the embodiments herein.

[0232] 药物组合物和施用方法 [0232] The pharmaceutical composition and method of administration

[0233] 本文所述的化合物可以使用本领域中可用的方法和本文公开的方法配制成药物组合物。 [0233] The compounds described herein using methods available in the art and methods disclosed herein formulated in a pharmaceutical composition. 本文公开的任何化合物可以呈适当的药物组合物提供并通过合适的施用途径施用。 Any of the compounds disclosed herein may be in an appropriate pharmaceutical composition is provided and administered by an appropriate administration route.

[0234] 本文提供的方法涵盖施用药物组合物,所述药物组合物含有至少一种如本文所述的化合物,包括通式I-VIII的化合物,适当时呈盐形式,单独使用或呈与一种或多种相容和药学上可接受的载体,例如稀释剂或佐剂,或者与另一抗癌剂组合的形式。 [0234] The methods provided herein encompass administration of a pharmaceutical composition, said pharmaceutical composition comprising at least one compound as described herein, including the compounds of formula I-VIII, where appropriate in salt form, and used alone or in a one or more pharmaceutically compatible and pharmaceutically acceptable carriers, diluents or adjuvants, for example in the form of, or in combination with another anticancer agent.

[0235] 在某些实施方案中,第二药剂可以与本文提供的化合物一起配制或包装。 [0235] In certain embodiments, the second agent can be formulated or packaged with the compound provided herein. 当然,第二药剂只在根据本领域的技术人员的判断,共同配制不会干扰任一药剂或者施用方法的活性时才与本文提供的化合物一起配制。 Of course, only the second agent according to the judgment of those skilled in the art, when formulated together does not interfere with any active agent or a method for administration formulated together with the compound provided herein. 在某些实施方案中,本文提供的化合物和第二药剂分开配制。 In certain embodiments, the compound provided herein and the second agent are formulated separately. 它们可以一起包装,或分开包装,以便于本领域的技术人员。 They may be packaged together, or packaged separately, so that those skilled in the art.

[0236] 在临床实践中,本文提供的活性剂可以通过任何常规途径、尤其是经口、肠胃外、 经直肠或通过吸入(例如呈气雾剂形式)施用。 [0236] In clinical practice the active agents provided herein can be prepared by any conventional route, in particular orally, parenterally, rectally or by inhalation (for example in the form of an aerosol) administration. 在某些实施方案中,本文提供的化合物经口施用。 In certain embodiments, the compound provided herein is administered orally.

[0237] 作为供口服用的固体组合物,可以利用片剂、丸剂、硬明胶胶囊、粉剂或颗粒。 [0237] As solid compositions for oral use, can be used tablets, pills, hard gelatin capsules, powders or granules. 在这些组合物中,活性产物与一种或多种惰性稀释剂或佐剂,例如蔗糖、乳糖或淀粉混合。 In these compositions, the active product, for example, mixed with one or more inert diluents or adjuvants as sucrose, lactose or starch.

[0238] 这些组合物可以包含除稀释剂以外的物质,例如润滑剂,例如硬脂酸镁或用于控制释放的包衣。 [0238] These compositions can comprise substances other than diluents, e.g. a lubricant such as magnesium stearate or for the controlled release coat.

[0239] 作为供口服用的液体组合物,可以利用药学上可接受的溶液、悬浮液、乳液、糖浆和酏剂,其含有例如水或液体石蜡等惰性稀释剂。 [0239] As liquid compositions for oral use, can be used pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs, containing inert diluents, e.g., water or liquid paraffin. 这些组合物还可以包含除稀释剂以外的物质,例如润湿剂、甜味剂或调味剂产品。 These compositions can also comprise substances other than diluents, for example wetting, sweetening or flavoring products.

[0240] 供肠胃外施用的组合物可以是乳液或无菌溶液。 [0240] The compositions for parenteral administration may be emulsions or sterile solutions. 作为溶剂或媒介物,可以利用丙二醇、聚乙二醇、植物油、尤其是橄榄油或可注射有机酯,例如油酸乙酯。 As solvent or vehicle, use may be propylene glycol, polyethylene glycol, vegetable oils, especially olive oil, or injectable organic esters, such as ethyl oleate. 这些组合物还可以含有佐剂,尤其是润湿剂、等渗剂、乳化剂、分散剂和稳定剂。 These compositions may also contain adjuvants, in particular wetting agents, isotonic agents, emulsifiers, dispersants and stabilizers. 灭菌可以用若干方式,例如使用细菌过滤器、通过辐射或通过加热来进行。 Sterilization can be used in several ways, for example using a bacteriological filter, by radiation or by heating. 其还可以呈无菌固体组合物形式制备,其在使用时可以溶解在无菌水或任何其它可注射的无菌介质中。 It may also be in the form of sterile solid compositions were prepared, which when in use can be dissolved in sterile water or any other sterile injectable medium.

[0241] 供经直肠施用的组合物是栓剂或直肠胶囊,其除了有效成分外还含有赋形剂,例如可可脂、半合成甘油酯或聚乙二醇。 [0241] The compositions for rectal administration are suppositories or rectal capsules composition, which in addition to the active ingredient, contain excipients, such as cocoa butter, semisynthetic glycerides or polyethylene glycols.

[0242] 组合物还可以是气雾剂。 [0242] The composition may also be aerosols. 对于呈液体气雾剂形式使用,组合物可以是稳定的无菌溶液或在使用时溶解于无热原的无菌水、盐水或任何其它药学上可接受的媒介物中的固体组合物。 For use in liquid aerosols, the compositions can be stable sterile solutions or in use was dissolved in sterile pyrogen-free water, saline or any other pharmaceutically acceptable vehicle is a solid composition. 对于呈意图直接吸入的干燥气雾剂的形式使用,将有效成分精细粉碎并与例如右旋糖酐、甘露糖醇或乳糖等水溶性固体稀释剂或媒介物组合。 For form was dried intended to be directly inhaled aerosols use, the active ingredient is finely pulverized and combined with the like for example dextran, mannitol or lactose, water-soluble solid diluent or vehicle.

[0243] 在某些实施方案中,本文提供的组合物是药物组合物或单一单位剂型。 [0243] In certain embodiments, a composition provided herein is a pharmaceutical composition or a single unit dosage form. 本文提供的药物组合物和单一单位剂型包含预防或治疗有效量的一种或多种预防剂或治疗剂(例如本文提供的化合物或其它预防剂或治疗剂)和典型地一种或多种药学上可接受的载体或赋形剂。 Provided herein pharmaceutical compositions and single unit dosage forms comprising a prophylactically or therapeutically effective amount of one or more prophylactic or therapeutic agents (e.g., a compound provided herein, or other prophylactic or therapeutic agent) and typically one or more pharmaceutically acceptable carrier or excipient. 在一特定实施方案中和这里,术语“药学上可接受”意指经联邦或州政府的管理机构批准或在美国药典或其它普遍认可的药典中列出用于动物中,且更尤其用于人类中。 And here, the term "pharmaceutically acceptable" In a particular embodiment, the means approved by the regulatory agency of the Federal or a state government or listed in the US Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more in particular for humans. 术语“载体”包括与治疗剂一起施用的稀释剂、佐剂(例如弗氏佐剂(Freund' s adjuvant)(完全和不完全))、赋形剂或媒介物。 The term "vector" includes a therapeutic agent is administered to a diluent, adjuvant (e.g., Freund's adjuvant (Freund 's adjuvant) (complete and incomplete)), excipient, or vehicle. 此类药物载体可以是无菌液体,例如水和油,包括石油、动物、植物或合成来源的油,例如花生油、豆油、矿物油、芝麻油等。 Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable oil, or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil and the like. 当药物组合物静脉内施用时水可以用作载体。 When intravenously administered pharmaceutical compositions may be used as the water carrier. 盐水溶液以及葡萄糖和丙三醇水溶液也可以用作液体载体,特别用于可注射溶液。 Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions. 合适的药物载体的实例描述于E .W. Mart in的“Remington's Pharmaceutical Sciences” 中。 Examples of suitable pharmaceutical carriers are described in E .W. Mart in the in "Remington's Pharmaceutical Sciences".

[0244] 典型的药物组合物和剂型包含一种或多种赋形剂。 [0244] Typical pharmaceutical compositions and dosage forms comprise one or more excipients. 合适的赋形剂是制药领域的技术人员所众所周知的,并且合适赋形剂的非限制性实例包括淀粉、葡萄糖、乳糖、蔗糖、明胶、麦芽、稻米、面粉、白垩、硅胶、硬脂酸钠、单硬脂酸甘油酯、滑石、氯化钠、脱脂奶粉、丙三醇、丙二醇、水、乙醇等。 Suitable pharmaceutical excipients are well known to the person skilled in the art and non-limiting examples of suitable excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate , glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol and the like. 特定赋形剂是否适合于掺入药物组合物或剂型中取决于本领域中众所周知的多种因素,包括(但不限于)剂型将施用于受试者的方式和剂型中的特定活性成分。 Whether a particular excipient is suitable for incorporation into a pharmaceutical composition or dosage form depends on a variety of factors well known in the art, including (but not limited to) the dosage form will be administered to a subject for a particular active ingredient and dosage forms of embodiment. 必要时,组合物或单一单位剂型还可以含有微量的润湿剂或乳化剂或pH值缓冲剂。 When necessary, the composition or single unit dosage form may also contain minor amounts of wetting or emulsifying agents or pH buffering agents.

[0245] 本文提供的无乳糖组合物可以包含本领域中众所周知并且例如在美国药典(USP) SP (XXI) /NF (XVI)中列出的赋形剂。 [0245] Lactose-free compositions provided herein may comprise excipients, for example, and are listed in the United States Pharmacopeia (USP) SP (XXI) / NF (XVI) are well known in the art. 一般说来,无乳糖组合物包含药学上相容和药学上可接受的量的活性成分、粘合剂/填充剂和润滑剂。 In general, lactose-free compositions comprise a pharmaceutically compatible and pharmaceutically acceptable amount of the active ingredient, a binder / filler and a lubricant. 示例性无乳糖剂型包含活性成分、微晶纤维素、预糊化淀粉和硬脂酸镁。 Exemplary lactose-free dosage forms comprise active ingredients, microcrystalline cellulose, pre-gelatinized starch, and magnesium stearate.

[0246] 本文中进一步涵盖包含活性成分的无水药物组合物和剂型,因为水可能促进一些化合物的降解。 [0246] Further encompassed herein are anhydrous pharmaceutical compositions and dosage forms comprising active ingredients, since water can facilitate the degradation of some compounds. 举例来说,作为一种模拟长期存储的方式,添加水(例如5 %)在制药领域中是广泛接受的,以测定随着时间推移例如货架期或制剂稳定性等特征。 For example, as a means of simulating long-term storage, the addition of water (e.g., 5%) in the pharmaceutical art is widely accepted, to determine the characteristic over time, for example, shelf life or stability of the formulation. 参见例如Jens T·Carstensen,Drug Stability:Principles&Practice,第2版,Marcel Dekker,New York, 1995,第379-380页。 See, eg, Jens T · Carstensen, Drug Stability: Principles & amp; Practice, 2nd ed., Marcel Dekker, New York, 1995, pp. 379-380. 实际上,水和热加速一些化合物的分解。 In effect, water and heat accelerate the decomposition of some compounds. 因此,水对制剂的作用具有重大意义,因为在制剂制造、处理、包装、存储、装运和使用期间通常会遭遇湿气和/或湿度。 Thus, the water on a formulation is of great significance, because in manufacturing preparations, often encounter moisture and / or humidity, handling, packaging, storage, shipment and during use.

[0247] 本文提供的无水药物组合物和剂型可以使用无水或低水分的成分和低湿气或低湿度条件来制备。 [0247] Anhydrous pharmaceutical compositions and dosage forms provided herein may be prepared using anhydrous or low moisture ingredients and low moisture or low humidity conditions. 如果在制造、包装和/或存储期间预期与湿气和/或湿度大量接触,那么包含乳糖和包含伯胺或仲胺的至少一种活性成分的药物组合物和剂型可以无水。 If during manufacturing, packaging, and with moisture during storage and expected / substantial contact / or humidity or that comprise lactose and a primary or secondary amine containing at least one active ingredient of the pharmaceutical compositions and dosage forms may be dry.

[0248] 无水药物组合物应经过制备和存储,使得其无水性质得以维持。 [0248] An anhydrous pharmaceutical composition should be prepared and after storage, such that its anhydrous nature is maintained. 因此,可以使用已知防止暴露于水的材料来包装无水组合物,以便其可以包括在合适的配制试剂盒中。 Thus, it is possible to use materials known to prevent exposure to water to anhydrous compositions are packaged so that it can be included in suitable formulated kits. 合适包装的实例包括(但不限于)密封箱、塑料、单位剂量容器(例如小瓶)、泡罩包装和条带包装。 Examples of suitable packaging include (but are not limited to) sealed boxes, plastics, unit dose containers (e.g., vials), blister packs, and strip packs.

[0249] 进一步提供了包含一种或多种降低活性成分分解速率的化合物的药物组合物和剂型。 [0249] provided further comprising one or more compounds that reduce the rate of decomposition of the active ingredient of the pharmaceutical compositions and dosage forms. 此类化合物在本文中称为“稳定剂”,包括(但不限于)抗氧化剂,例如抗坏血酸、PH值缓冲剂或盐缓冲剂。 Such compounds are referred to as "stabilizers" herein, including (but not limited to) anti-oxidants, such as ascorbic acid, PH value buffers, or salt buffers.

[0250] 药物组合物和单一单位剂型可以采取溶液、悬浮液、乳液、片剂、丸剂、胶囊、粉剂、 持续释放制剂等形式。 [0250] The pharmaceutical compositions and single unit dosage forms can take the solutions, suspensions, emulsions, tablets, pills, capsules, powders, sustained release formulations and the like. 口服制剂可以包括标准载体,例如药物级甘露糖醇、乳糖、淀粉、硬脂酸镁、糖精钠、纤维素、碳酸镁等。 Oral formulation can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, and the like. 此类组合物和剂型将含有预防或治疗有效量的预防剂或治疗剂,在某些实施方案中,呈纯化形式的预防剂或治疗剂,以及合适量的载体,以便提供适于施用于受试者的形式。 Such compositions and dosage forms containing a prophylactically or therapeutically effective amount of a prophylactic or therapeutic agent, in certain embodiments, in purified form prophylactic or therapeutic agent, together with a suitable amount of carrier so as to provide suitable for administration by in the form of those tested. 制剂将适合施用模式。 The formulations suitable for the mode of administration. 在某一实施方案中,药物组合物或单一单位剂型是无菌的并且呈适于施用于受试者,例如动物受试者,例如哺乳动物受试者,例如受试人的形式。 In certain embodiments, the pharmaceutical compositions or single unit dosage form is sterile and suitable for administration to a subject, such as an animal subject, such as a mammalian subject, e.g. in the form of a human subject.

[0251] 药物组合物被配制成与其预期施用途径相容。 [0251] pharmaceutical composition is formulated to be compatible with its intended route of administration. 施用途径的实例包括(但不限于)肠胃外,例如静脉内、皮内、皮下、肌肉内、皮下、经口、经颊、舌下、吸入、鼻内、经皮、局部、经粘膜、肿瘤内、滑膜内和经直肠施用。 Examples of routes of administration include (but are not limited to) parenteral, e.g., intravenous, intradermal, subcutaneous, intramuscular, subcutaneous, oral, buccal, sublingual, inhalation, intranasal, transdermal, topical, transmucosal, tumor inner, intrasynovial, and rectal administration. 在一特定实施方案中,组合物根据常规程序配制成适合于静脉内、皮下、肌肉内、经口、鼻内或局部施用于人类的药物组合物。 In a particular embodiment, the composition is formulated for intravenous, subcutaneous accordance with routine procedures, intramuscular, oral, intranasal or topical administration to a human a pharmaceutical composition. 在一个实施方案中, 药物组合物根据常规程序来配制以供皮下施用于人。 In one embodiment, the pharmaceutical composition is formulated in accordance with routine procedures for subcutaneous administration to a human. 典型地,用于静脉内施用的组合物是于无菌等渗的水性缓冲液中的溶液。 Typically, compositions for intravenous administration are solutions in sterile isotonic aqueous buffer in. 需要时,组合物还可以包括增溶剂和局部麻醉剂,例如利诺卡因(Iignocamne),以缓解注射部位的疼痛。 When necessary, the composition may also include a solubilizing agent and a local anesthetic such as lignocaine (Iignocamne), to ease pain at the injection site.

[0252] 剂型的实例包括(但不限于):片剂;囊片;胶囊,例如软弹性明胶胶囊;扁囊剂;糖锭;口含锭;分散液;栓剂;软膏;糊剂(膏状药);糊状物;粉剂;敷料;乳膏;膏药;溶液;贴片; 气雾剂(例如鼻喷雾或吸入剂);凝胶;适合于经口或经粘膜施用于受试者的液体剂型,包括悬浮液(例如水性或非水性液体悬浮液、水包油乳液或油包水液体乳液)、溶液和酏剂;适合于肠胃外施用于受试者的液体剂型;和无菌固体(例如结晶或非晶固体),其可以复原,从而提供适合于肠胃外施用于受试者的液体剂型。 [0252] Examples of dosage forms include (but are not limited to): tablets; caplets; capsules, such as soft elastic gelatin capsules; flat sachets; lozenges; lozenges; dispersion; suppositories; ointments; pastes (paste drugs); paste; powders; dressings; creams; plaster; solution; patch; a liquid suitable for oral or mucosal administration to a subject; aerosols (e.g., nasal sprays or inhalers); gel dosage forms, including suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil in water emulsion or a water in oil liquid emulsions), solutions, and elixirs; suitable for parenteral liquid dosage form is administered to a subject; and sterile solids ( for example, crystalline or amorphous solids) that can be restored, thereby to provide a suitable liquid dosage forms for parenteral administration to a subject.

[0253] 本文提供的剂型的组成、形状和类型将典型地视其用途而变化。 [0253] composition, shape, and type of dosage forms provided herein will typically vary depending on their use. 举例来说,用于初步治疗癌症的剂型可以含有较大量的一种或多种活性成分,其包含的一种或多种活性成分的量比用于相同癌症的维持治疗的剂型大。 For example, dosage forms for the treatment of cancer the initial dosage forms may contain larger amounts of one or more active ingredients, comprising than one or more active ingredients for the maintenance treatment of the same cancers is large. 类似地,肠胃外剂型可以含有较小量的一种或多种活性成分,其包含的活性成分的量比用于治疗相同疾病或病症的口服剂型小。 Similarly, a parenteral dosage form may contain smaller amounts of one or more active ingredients comprising active ingredients than for small treat the same disease or disorder of the oral dosage form. 本领域的技术人员将显而易见将使本文中涵盖的特定剂型彼此不同的这些和其它方式。 Those skilled in the art would be apparent to a particular dosage form contemplated herein, and these various other ways to each other. 参见例如Remington's Pharmaceutical Sciences,第20版,Mack Publishing,Easton PA (2000) 〇 See, for example, Remington's Pharmaceutical Sciences, 20th ed., Mack Publishing, Easton PA (2000) square

[0254] —般来说,组合物的成分分开供应或一起混合在单位剂型中,例如呈干燥的冻干粉剂或无水浓缩物,于例如安瓿或香囊等指示活性剂的量的密闭容器中。 [0254] - In general, the components of the composition are supplied separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water free concentrate in a sealed container for example an ampoule or the like an amount of the active agent indicated sachets in. 在组合物通过输液施用的情况下,其可以用含有无菌医药级水或盐水的输液瓶分配。 In the case where the composition is administered by infusion, it can be allocated with an infusion bottle containing sterile pharmaceutical grade water or saline. 在组合物通过注射施用的情况下,可以提供注射用无菌水或盐水的安瓿以便成分可以在施用前混合。 In the case where the composition is administered by injection, an ampoule for injection can be provided so that sterile water or saline component may be mixed prior to administration.

[0255]典型的剂型包含在每日约0. Img到约IOOOmg范围内的本文提供的化合物或其药学上可接受的盐、溶剂化物或水合物,呈一日一次单一剂量在早晨给与或在一天中与食物一起分次给与。 [0255] Typical dosage forms comprise a compound of the daily dosage of about 0. Img herein to provide within the range of about IOOOmg or a pharmaceutically acceptable salt, solvate or hydrate thereof, given as a single dose once a day in the morning or several times during the day to give with food. 特定剂型可以具有约0.1、0.2、0.3、0.4、0.5、1.0、2.0、2.5、5.0、10.0、15.0、 20·0、25·0、50·0、100、200、250、500或IOOOmg 活性化合物。 The particular dosage form may have about 0.1,0.2,0.3,0.4,0.5,1.0,2.0,2.5,5.0,10.0,15.0, 0,25 · 20 · 0,50 · 0,100,200,250,500 active compound or IOOOmg .

[0256] 口服剂型 [0256] Oral dosage forms

[0257] 适合于口服的药物组合物可以呈离散剂型呈现,例如但不限于片剂(例如咀嚼片)、囊片、胶囊和液体(例如风味糖楽)。 [0257] Pharmaceutical compositions suitable for oral administration may be presented as a discrete dosage forms, such as, but not limited to, tablets (e.g., chewable tablets), caplets, capsules, and liquids (e.g., flavored sugar yue). 此类剂型含有预定量的活性成分,并且可以通过本领域的技术人员众所周知的制药方法来制备。 Such dosage forms contain predetermined amounts of active ingredients, and may be prepared by those skilled in the art of pharmacy well known methods. 一般参见Remington' s Pharmaceutical Sciences,第20版,Mack Publishing,Easton PA(2000)〇 See generally, Remington 's Pharmaceutical Sciences, 20th ed., Mack Publishing, Easton PA (2000) square

[0258] 在某些实施方案中,口服剂型是固体并在无水条件下用无水成分制备,如本文中详细描述。 [0258] In certain embodiments, oral dosage forms are solid and prepared with anhydrous ingredients under anhydrous conditions, as described in detail herein. 但是,本文提供的组合物的范围延伸超过无水的固体口服剂型。 However, the scope of the compositions provided herein extends beyond anhydrous, solid oral dosage forms. 因而,本文描述其它形式。 Thus, other forms are described herein.

[0259] 典型的口服剂型是通过根据常规的配药技术将活性成分组合,与至少一种赋形剂密切混合来制备。 [0259] A typical oral dosage form is prepared by intimately mixed with at least one excipient according to conventional pharmaceutical techniques by the combination of the active ingredient. 赋形剂可以采取多种形式,取决于施用所需的制剂形式。 Excipients can take a wide variety of forms depending on the form of preparation desired administration. 举例来说,适用于口服液体或气雾剂剂型中的赋形剂包括(但不限于)水、二醇、油、醇、调味剂、防腐剂和着色剂。 For example, suitable for use in oral liquid or aerosol dosage forms excipients include (but are not limited to) water, glycols, oils, alcohols, flavoring agents, preservatives, and coloring agents. 适用于固体口服剂型(例如粉剂、片剂、胶囊和囊片)的赋形剂的实例包括(但不限于) 淀粉、糖、微晶纤维素、稀释剂、成粒剂、润滑剂、粘合剂和崩解剂。 Examples of excipients suitable for use in solid oral dosage forms (e.g., powders, tablets, capsules, and caplets) include, (but are not limited to) starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders and disintegrating agents.

[0260] 由于片剂和胶囊易于施用,所以其代表最有利的口服单位剂型,在这种情况下,采用固体赋形剂。 [0260] Because of their ease of administration, tablets and capsules, which thus represent the most advantageous oral dosage unit form, in which case solid excipients are employed. 必要时,片剂可以通过标准的水性或非水性技术来包覆包衣。 If necessary, tablets may be coated by standard aqueous or nonaqueous techniques. 此类剂型可以通过任何制药方法来制备。 Such dosage forms can be prepared by any of the methods of pharmacy. 一般说来,药物组合物和剂型是通过将活性成分与液体载体、精细粉碎的固体载体或两者均匀和密切混合,接着必要时使产物成形成所需呈递形式来制备。 In general, pharmaceutical compositions and dosage forms by mixing the active ingredient with liquid carriers, finely divided solid carriers or both uniformly and intimately mixed, and then the product is prepared, if necessary, to form the desired presentation form.

[0261] 举例来说,片剂可以通过压缩或模制来制备。 [0261] For example, tablets may be prepared by compression or molding. 压缩片剂可以通过在合适机器中压缩例如粉末或颗粒等呈易流动形式的活性成分,任选地与赋形剂混合来制备。 Compressed tablets may be prepared, optionally mixed with an excipient by compressing in a suitable machine such as a powder or granules, flowable and the like as a form of the active ingredient. 模制片剂可以通过在合适机器中模制被惰性液体稀释剂润湿的粉末状化合物的混合物来制备。 Molded tablets may be prepared by molding the mixture is moistened with an inert liquid diluent powdered compound in a suitable machine.

[0262] 可以用于口服剂型的赋形剂的实例包括(但不限于)粘合剂、填充剂、崩解剂和润滑剂。 Examples [0262] can be used in oral dosage form excipients include (but are not limited to) binders, fillers, disintegrants, and lubricants. 适用于药物组合物和剂型中的粘合剂包括(但不限于)玉米淀粉、马铃薯淀粉或其它淀粉、明胶、天然和合成胶(例如阿拉伯胶、褐藻酸钠、褐藻酸、其它褐藻酸盐、粉末状黄蓍胶、瓜耳豆胶)、纤维素和其衍生物(例如乙基纤维素、乙酸纤维素、羧甲基纤维素钙、羧甲基纤维素钠)、聚乙烯基吡咯烷酮、甲基纤维素、预糊化淀粉、羟丙基甲基纤维素(例如No. 2208、2906、2910)、微晶纤维素和其混合物。 Suitable for pharmaceutical compositions and dosage forms of the binders include (but not limited to) cornstarch, potato starch, or other starches, gelatin, natural and synthetic gums (such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum), cellulose and derivatives thereof (e.g. ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose, pre-gelatinized starch, hydroxypropyl methyl cellulose (e.g. No. 2208,2906,2910), microcrystalline cellulose, and mixtures thereof.

[0263] 适用于本文公开的药物组合物和剂型中的填充剂的实例包括(但不限于)滑石、碳酸钙(例如颗粒或粉末)、微晶纤维素、粉末状纤维素、葡萄糖结合剂、高岭土、甘露糖醇、硅酸、山梨糖醇、淀粉、预糊化淀粉和其混合物。 [0263] Examples of suitable herein disclosed pharmaceutical compositions and dosage forms of fillers include (but are not limited to), talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof. 药物组合物中的粘合剂或填充剂典型地以药物组合物或剂型的约50重量百分比至约99重量百分比存在。 The pharmaceutical composition of binder or filler is typically present in from about 50 weight of the pharmaceutical composition or dosage form percent to about 99 weight percent is present.

[0264] 微晶纤维素的合适形式包括(但不限于)以AVICEL PH 10UAVICEL PH 103、 AVICEL RC 581、AVICEL PH 105 (可以从FMC公司(American Viscose Division,Avicel SaleS,MarcuS H〇〇k,PA)获得)出售的物质。 Suitable forms of [0264] the microcrystalline cellulose include (but are not limited to) for AVICEL PH 10UAVICEL PH 103, AVICEL RC 581, AVICEL PH 105 (available from FMC Corporation (American Viscose Division, Avicel SaleS, MarcuS H〇〇k, PA ) to obtain material) sold. 一种特定粘合剂是以AVICEL RC 581出售的微晶纤维素与羧甲基纤维素钠的混合物。 One particular binder is a mixture of microcrystalline cellulose and sodium carboxymethyl cellulose, AVICEL RC 581 for sale. 合适的无水或低水分赋形剂或添加剂包括AVICEL PH 103™ 和Starch 1500LM。 Suitable anhydrous or low moisture excipients or additives include AVICEL PH 103 ™ and Starch 1500LM.

[0265] 崩解剂用于组合物中以使片剂在暴露于含水环境时崩解。 [0265] Disintegrants are used in the tablet composition to disintegrate when exposed to an aqueous environment. 含有太多崩解剂的片剂可能在存储时崩解,而那些含有太少崩解剂的片剂可能不以所需速率或在所需条件下崩解。 Tablets that contain too much disintegrant may disintegrate in storage, while those that contain too little tablet disintegrating agents may not disintegrate at a desired rate or under the desired conditions. 因此,应将充分量的崩解剂用于形成固体口服剂型,其量既不太多也不太少以致不利地改变活性成分的释放。 Thus, a sufficient amount of disintegrant should be used to form solid oral dosage forms, in an amount that neither too much nor too little to detrimentally alter the release of the active ingredient. 所用崩解剂的量基于配制类型而变,并且一般技术者容易了解。 The amount of disintegrant used vary based on the type of formulation, and is readily apparent to those ordinary skill. 典型的药物组合物包含约0.5至约15重量百分比崩解剂,特别是约1到约5重量百分比崩解剂。 Typical pharmaceutical compositions comprise from about 0.5 to about 15 weight percent of disintegrant, particularly from about 1 to about 5 weight percent of disintegrant.

[0266] 可以用于药物组合物和剂型的崩解剂包括(但不限于)琼脂、褐藻酸、碳酸钙、微晶纤维素、交联羧甲基纤维素钠、交联聚维酮、聚克立林钾、羟基乙酸淀粉钠、马铃薯或木薯淀粉、预糊化淀粉、其它淀粉、粘土、其它褐藻胶、其它纤维素、树胶和其混合物。 [0266] can be used in pharmaceutical compositions and dosage forms of disintegrants include (but are not limited to) agar, alginic acid, calcium carbonate, microcrystalline cellulose, cross-linked sodium carboxymethylcellulose, cross-linked povidone, poly polacrilin potassium, sodium starch glycolate, potato or tapioca starch, pre-gelatinized starch, other starches, clays, other algins, other celluloses, gums, and mixtures thereof.

[0267] 可以用于药物组合物和剂型中的润滑剂包括(但不限于)硬脂酸钙、硬脂酸镁、矿物油、轻质矿物油、甘油、山梨糖醇、甘露糖醇、聚乙二醇、其它二醇、硬脂酸、十二烷基硫酸钠、滑石、氢化植物油(例如花生油、棉籽油、葵花油、芝麻油、橄榄油、玉米油和豆油)、硬脂酸锌、油酸乙酯、月桂酸乙酯、琼脂和其混合物。 [0267] can be used in pharmaceutical compositions and dosage forms lubricants include (but are not limited to) calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil and soybean oil), zinc stearate, oleyl ethyl laurate, agar, and mixtures thereof. 额外润滑剂包括例如syloid硅胶(AER0SIL 200,Baltimore (MD)的WRGrace公司制造)、合成二氧化娃的凝结气雾剂(Plano (TX)的Degussa公司销售)、CAB 0 SIL (Boston (MA)的Cabot公司出售的热解二氧化硅产品)和其混合物。 Additional lubricants include, for example, a syloid silica gel (AER0SIL 200, Baltimore (MD) of WRGrace Co., Ltd.), a coagulated aerosol of synthetic baby dioxide (Plano (TX) is sold by Degussa AG), CAB 0 SIL (Boston (MA) of Cabot Corporation fumed silica sold products), and mixtures thereof. 如果确实需要,那么润滑剂典型地以小于其掺入的药物组合物或剂型的约1重量百分比的量使用。 Indeed, if desired, the lubricant is typically less than a pharmaceutical composition or dosage form which is incorporated in an amount from about 1 weight percent to use.

[0268] 延迟释放剂型 [0268] Delayed Release Dosage Forms

[0269] 例如本文提供的化合物等活性成分可以通过控制释放方式或通过本领域的一般技术人员清楚了解的递送装置来施用。 [0269] For example a compound provided herein and other active ingredients can be administered by controlled release means or by delivery devices by those skilled in the art a clear understanding. 实例包括(但不限于)以下中描述的方式和装置:美国专利No 3,845,770;3,916,899;3,536,809;3,598,123;和4,008,719;5,674,533;5,059, 595;5,591,767;5,120,548;5,073,543;5,639,476;5,354,556;5,639,480;5,733,566;5, 739,108;5,891,474;5,922,356;5,972,891;5,980,945;5,993,855;6,045,830;6,087, 324;6,113,943;6,197,350;6,248,363;6,264,970;6,267,981;6,376,461;6,419,961;6, 589,548; 6,613,358;和6,699,500;每个专利以引用的方式整体并入本文中。 Examples include (but are not limited to) the following method and apparatus described in: U.S. Patent No 3,845,770; 3,916,899; 3,536,809; 3,598,123; and 4,008,719; 5,674,533; 5,059, 595; 5,591,767; 5,120,548; 5,073 , 543; 5,639,476; 5,354,556; 5,639,480; 5,733,566; 5, 739,108; 5,972,891;; 5,891,474; 5,922,356 5,980,945; 5,993,855; 6,045,830; 6,087, 324; 6,113,943; 6,197,350 ; 6,248,363; 6,264,970; 6,267,981; 6,376,461; 6,419,961; 6, 589,548; 6,613,358; and 6,699,500; each incorporated by reference in its entirety herein. 此类剂型可以用于提供一种或多种活性成分的缓慢或控制释放,其使用例如变化比例的羟丙基甲基纤维素、其它聚合物基质、凝胶、渗透膜、渗透系统、多层包衣、微粒、脂质体、微球体或其组合以提供所需释放特征。 Such dosage forms can be used to provide slow or controlled release of one or more active ingredients using, for example hydroxypropylmethyl cellulose in varying proportions, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or a combination thereof to provide the desired release profile. 本领域的一般技术人员已知的合适的控制释放制剂包括本文所述的那些控制释放制剂,容易选择其用于本文提供的活性成分。 Suitable controlled-release formulations are generally known to those skilled in the art including those described herein, controlled release formulations, the active ingredient readily selected for use herein. 因此,本文中涵盖适合于口服的单个单位剂型,例如但不限于适合于控制释放的片剂、胶囊、明胶胶囊和囊片。 Thus, herein encompasses single unit dosage forms suitable for oral administration, for example but not limited to controlled release tablets, capsules, gelatin capsules and caplets.

[0270] 所有的控制释放医药产品都具有改善药物疗法,使得疗效超越其不受控制的对应药物所实现的疗效的共同目标。 [0270] All controlled-release pharmaceutical products have improved drug therapy, so that its effect beyond the common goal of uncontrolled correspond to the efficacy of the drug achieved. 理想地,在医疗中经过最佳设计的控制释放制剂的使用的特点在于用最少的原料药在最短的时间内治愈或控制病状。 Desirably, through the use of an optimally designed controlled release preparation in medical treatment is characterized cure or control the condition in the shortest time with the least drug. 控制释放制剂的优点包括延长药物活性、降低给药频率和增加受试者的顺应性。 Advantages of controlled-release formulations include extended activity of the drug, reduced dosage frequency, and increased subject compliance. 另外,控制释放制剂可以用于影响作用开始时间或其它的特征,例如药物的血液水平,因此会影响副(例如不利)作用的发生。 Further, controlled release formulations can be used, or start time influence other characteristics, such as blood levels of the drug, thus affecting the sub occur (e.g., adverse) effects.

[0271] 大部分的控制释放制剂被设计成最初释放迅速产生所需治疗作用的量的药物(活性成分),并且逐渐和不断地释放其它量的药物以长时间维持此治疗或预防作用水平。 [0271] Most controlled-release formulations are designed to initially release rapid drug (active ingredient) of the desired amount of the therapeutic effect, and gradually and continually release of other amounts of drug to maintain this for a long time therapeutic or prophylactic effect level. 为了维持药物在身体内的此恒定水平,药物须以将替换从身体代谢和分泌的量的药物的速率从剂型释放。 In order to maintain this constant level of drug in the body, the drug must be in order to replace the amount of drug metabolism and secreted from the body of the release rate of the dosage form. 活性成分的控制释放可以通过多种条件来刺激,这些条件包括(但不限于)PH值、 温度、酶、水或其它生理条件或化合物。 Controlled release of active ingredient can be stimulated by various conditions, which include (but are not limited to) PH value, temperature, enzymes, water, or other physiological conditions or compounds.

[0272] 在某些实施方案中,药物可以使用静脉内输液、可植入的渗透栗、经皮贴片、脂质体或其它施用模式来施用。 [0272] In certain embodiments, the drug may be used intravenous infusion, an implantable osmotic Li, transdermal patch, liposomes, or other modes of administration to administration. 在某些实施方案中,可以使用栗(参见Sef ton,CRC Crit · Ref · Biomed · Eng · 14:201 (1987) ; Buchwald等人,Surgery 88: 507 (1980) ; Saudek等人,N.Engl.J.Med.321:574(1989))。 In certain embodiments, Li may be used (see Sef ton, CRC Crit · Ref · Biomed · Eng · 14: 201 (1987); Buchwald et al, Surgery 88: 507 (1980); Saudek et al, N. Engl .J.Med.321: 574 (1989)). 在另一实施方案中,可以使用聚合物材料。 In another embodiment, polymeric materials can be used. 在又一实施方案中,控制释放系统可以放在受试者中由执业医生确定的适当部位,因此仅仅需要全身剂量的一小部分(参见例如Goodson,Medical Applications of Controlled Release,第2 卷,第115-138页(1984))。 In yet another embodiment, a controlled release system can be placed in a suitable site in a subject determined by the practitioner, so only needs a fraction of the systemic dose (see, e.g., Goodson, Medical Applications of Controlled Release, vol. 2, pp. 115-138 (1984)). 其它控制释放系统论述于Langer的评述(Science 249:1527-1533 (1990))中。 Other controlled release systems are discussed in the commentary by Langer (Science 249: 1527-1533 (1990)) in the. 活性成分可以分散在例如以下等固体内基质中:聚甲基丙烯酸甲酯;聚甲基丙烯酸丁酯;增塑或未增塑聚氯乙烯;增塑尼龙;增塑聚对苯二甲酸乙二醇酯;天然橡胶; 聚异戊二烯;聚异丁烯;聚丁二烯;聚乙烯;乙烯-乙酸乙烯酯共聚物;硅酮橡胶;聚二甲基硅氧烷;硅酮碳酸酯共聚物;亲水性聚合物,例如丙烯酸酯和甲基丙烯酸酯的水凝胶;胶原蛋白;交联聚乙烯醇和交联的部分水解的聚乙酸乙烯酯,所述固体内基质被不溶于体液的外聚合物膜包围,所述外聚合物膜例如聚乙烯、聚丙烯、乙烯/丙烯共聚物、乙烯/丙烯酸乙酯共聚物、乙烯/乙酸乙烯酯共聚物、硅酮橡胶、聚二甲基硅氧烷、氯丁橡胶、氯化聚乙烯、聚氯乙烯、氯乙烯与乙酸乙烯酯的共聚物、偏二氯乙烯、乙烯和丙烯、离聚物、聚对苯二甲酸乙二醇酯、丁基橡胶、氯醇橡胶、乙烯/乙烯醇共聚物、乙烯/乙 The active ingredient may be dispersed in, for example, the solid matrix like the following: polymethyl methacrylate; polybutyl methacrylate; plasticized or unplasticized polyvinylchloride; plasticized nylon; plasticized polyethyleneterephthalate alcohol esters; natural rubber; polyisoprene; polyisobutylene; polybutadiene; polyethylene; ethylene - vinyl acetate copolymers; silicone rubbers; polydimethylsiloxanes; silicone carbonate copolymers; hydrophilic polymers, such as hydrogels acrylate and methacrylate; collagen; partially hydrolyzed crosslinked polyvinyl alcohol and crosslinked poly vinyl acetate, the solid inner matrix is ​​insoluble in body fluids outside the polymerization film surrounds the outer polymeric film such as polyethylene, polypropylene, ethylene / propylene copolymers, ethylene / ethyl acrylate copolymers, ethylene / vinyl acetate copolymers, silicone rubbers, polydimethylsiloxanes , chloroprene rubber, chlorinated polyethylene, polyvinylchloride, vinylchloride copolymers with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber , epichlorohydrin rubbers, ethylene / vinyl alcohol copolymer, ethylene / b 乙烯酯/乙烯醇三元共聚物和乙烯/乙烯氧基乙醇共聚物。 Vinyl acetate / vinyl alcohol terpolymer, and ethylene / vinyloxyethanol copolymer. 接着活性成分在释放速率控制步骤中扩散穿过外聚合物膜。 Then the active ingredient diffuses through the outer step in the release rate controlling polymer membrane. 活性成分在此类肠胃外组合物中的百分比高度依赖于其特定性质以及受试者的需要。 The percentage of active ingredient in such parenteral compositions is highly dependent on the nature of the particular needs of the subject.

[0273] 肠胃外剂型 [0273] Parenteral dosage forms

[0274] 在某些实施方案中,提供了肠胃外剂型。 [0274] In certain embodiments, a parenteral dosage forms. 肠胃外剂型可以通过多种途径施用于受试者,这些途径包括(但不限于)皮下、静脉内(包括快速浓注)、肌肉内和动脉内。 Parenteral dosage forms can be administered to a subject by various routes, such routes include (but are not limited to), subcutaneous, intravenous (including bolus injection), intramuscular, and intraarterial. 因为其施用典型地绕过受试者对污染物的天然防御,所以肠胃外剂型典型地无菌或能够在施用于受试者前被灭菌。 Administration because it typically bypasses subjects' natural defenses against contaminants, parenteral dosage forms are typically sterile or capable of being sterilized prior to administration to the subject. 肠胃外剂型的实例包括(但不限于)准备注射的溶液、准备溶解或悬浮于药学上可接受的媒介物中以供注射的干燥产物、准备注射的悬浮液和乳液。 Examples of parenteral dosage forms include (but are not limited to) solutions ready for injection, preparation dissolved or suspended in a pharmaceutically acceptable vehicle for use in a dry product for injection, suspensions ready for injection, and emulsions.

[0275] 可以用于提供肠胃外剂型的合适媒介物是本领域的技术人员众所周知的。 [0275] may be used to provide parenteral dosage forms suitable vehicles are well known to persons skilled in the art. 实例包括(但不限于):USP注射用水;水性媒介物,例如但不限于氯化钠注射液、林格氏注射液、葡萄糖注射液、葡萄糖和氯化钠注射液以及乳酸化林格氏注射液;水溶性媒介物,例如但不限于乙醇、聚乙二醇和聚丙二醇;和非水性媒介物,例如但不限于玉米油、棉籽油、花生油、芝麻油、油酸乙酯、肉豆蔻酸异丙酯和苯甲酸苄酯。 Examples include (but are not limited to): USP water for injection; an aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection solution; water soluble vehicles, such as, but not limited to, ethyl alcohol, polyethylene glycol and polypropylene glycol; and non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate esters and benzyl benzoate.

[0276] 增加本文公开的一种或多种活性成分的溶解性的化合物也可以掺入肠胃外剂型中。 [0276] increase the solubility of one or more active ingredients disclosed herein can also be incorporated into the compounds of the parenteral dosage forms.

[0277] 经皮、局部和经粘膜剂型 [0277] transdermal, topical, and mucosal dosage forms

[0278] 还提供了经皮、局部和经粘膜剂型。 [0278] also provides transdermal, topical, and mucosal dosage forms. 经皮、局部和经粘膜剂型包括(但不限于)眼用溶液、喷雾、气雾剂、乳膏、洗剂、软膏、凝胶、溶液、乳液、悬浮液或本领域的技术人员已知的其它形式。 Transdermal, topical, and mucosal dosage forms include (but are not limited to) an ophthalmic solutions, sprays, aerosols, creams, lotions, ointments, gels, solutions, emulsions, suspensions, or known to those skilled in the other forms. 参见例如Remington' s Pharmaceutical Sciences,第16、18和20版,Mack Publishing,Easton PA (1980年、1990年和2000年);和Introduction to Pharmaceutical Dosage Forms,第4版,Lea和Febiger ,Philadelphia (1985)。 See, for example, Remington 's Pharmaceutical Sciences, Edition 16, 18 and 20, Mack Publishing, Easton PA (1980, 1990 and 2000); and Introduction to Pharmaceutical Dosage Forms, 4th ed., Lea and Febiger, Philadelphia (1985 ). 适合于治疗口腔内粘膜组织的剂型可以被配制成嗽口水或口服凝胶。 Suitable for treating mucosal tissues within the oral dosage forms may be formulated as mouthwashes or oral gels. 此外,经皮剂型包括“药库型”或“基质型”贴片,其可以施加于皮肤并戴着持续特定的时间以允许所需量的活性成分渗透。 Further, transdermal dosage forms include "storeroom type" or "matrix type" patches, which can be applied to the skin and wearing for a certain time to permit the penetration of a desired amount of the active ingredient.

[0279] 可以用于提供本文中涵盖的经皮、局部和经粘膜剂型的合适赋形剂(例如载体和稀释剂)和其它物质是制药领域的技术人员众所周知的,并且取决于将施加特定药物组合物或剂型的特定组织。 [0279] may be used to provide transdermal contemplated herein, topical, and mucosal dosage forms suitable excipients (e.g., carriers and diluents) and other materials are well known to those of skill in the pharmaceutical and applied depending on the particular drug composition or dosage form specific tissue. 考虑到这一事实,典型的赋形剂包括(但不限于)水、丙酮、乙醇、乙二醇、丙二醇、丁1,3二醇、肉豆蔻酸异丙酯、棕榈酸异丙酯、矿物油和其混合物,以形成洗剂、 酊剂、乳膏、乳液、凝胶或软膏,这些赋形剂是无毒的并且是药学上可接受的。 Taking into account this fact, typical excipients include (but are not limited to) water, acetone, ethanol, ethylene glycol, propylene glycol, butane 1,3 diol, isopropyl myristate, isopropyl palmitate, mineral oils and mixtures thereof to form lotions, tinctures, creams, emulsions, gels or ointments, such excipients are non-toxic and pharmaceutically acceptable. 必要时,保湿剂或湿润剂也可以加入药物组合物和剂型。 If necessary, moisturizers or humectants can also be added to pharmaceutical compositions and dosage forms. 此类额外成分的实例是本领域中众所周知的。 Examples of such additional ingredients are well known in the art. 参见例如Remington' s Pharmaceutical Sciences,第16、18和20版,MackPublishing, Easton PA (1980年、1990年和2000年)。 See, for example, Remington 's Pharmaceutical Sciences, Edition 16, 18 and 20, MackPublishing, Easton PA (1980, 1990 and 2000).

[0280] 取决于有待治疗的特定组织,可以在用所提供的活性成分治疗之前、同时或之后使用额外的组分。 [0280] Depending on the particular tissue to be treated, it can be provided by prior treatment of the active ingredient, simultaneously with or after the use of additional components. 举例来说,渗透增强剂可以用于帮助递送活性成分到组织。 For example, penetration enhancers can be used to assist in delivering active ingredients to the tissue. 合适的渗透增强剂包括(但不限于):丙酮;多种醇,例如乙醇、油醇和四氢糠醇;烷基亚砜,例如二甲亚砜; 二甲基乙酰胺;二甲基甲酰胺;聚乙二醇;吡咯烷酮,例如聚乙烯吡咯烷酮;Ko 11 i don级别(聚维酮(Povidone)、聚维酮(Polyvidone));脲;和多种水溶性或不溶性糖酯,例如Tween 80 (聚山梨醇酯80)和Span 60 (山梨醇酐单硬脂酸酯)。 Suitable penetration enhancers include (but are not limited to): acetone; various alcohols such as ethanol, oleyl alcohol and tetrahydrofurfuryl alcohol; alkyl sulfoxides, such as dimethyl sulfoxide; dimethylacetamide; dimethylformamide; polyethylene glycol; pyrrolidones such as polyvinylpyrrolidone; Ko 11 i don level (povidone (povidone), povidone (polyvidone)); urea; and various water soluble or insoluble sugar esters such as Tween 80 (poly polysorbate 80) and Span 60 (sorbitan monostearate).

[0281] 还可以调节药物组合物或剂型或者药物组合物或剂型所施加的组织的pH值以增强一种或多种活性成分的递送。 [0281] may further adjust the pH of the pharmaceutical composition or dosage form, or a pharmaceutical composition or dosage form is applied to tissue to enhance delivery of one or more active ingredients. 类似地,可以调节溶剂载体的极性、其离子强度或张力以增强递送。 Similarly, the polarity of a solvent carrier, its ionic strength, or tonicity to enhance delivery. 例如硬脂酸酯等化合物还可以加入药物组合物或剂型中以有利地改变一种或多种活性成分的亲水性或亲油性,从而增强递送。 And other compounds such as stearates can also be added to pharmaceutical compositions or dosage forms to advantageously alter one or more hydrophilic or lipophilic active ingredients, so as to enhance delivery. 在这点上,硬脂酸酯可以用作制剂的脂质媒介物,用作乳化剂或表面活性剂,以及用作递送增强剂或渗透增强剂。 In this regard, stearates can serve as a lipid vehicle formulation, as an emulsifying agent or surfactant, and as a delivery-enhancing or penetration-enhancing agent. 活性成分的不同的盐、 水合物或溶剂化物可以用于进一步调节所得组合物的性质。 Different salts, hydrates or solvates of the active ingredients may be used to further adjust the properties of the resulting composition.

[0282] 剂量和单位剂型 [0282] The unit dosage form and dosage

[0283] 在人类治疗学中,医生将根据预防性治疗或治愈性治疗以及根据年龄、体重、癌症阶段和对有待治疗的受试者来说特定的其它因素来确定其认为最适当的剂量。 [0283] In human therapeutics, and the doctor will determine the most appropriate dose based on it deems prophylactic treatment or curative treatment based on age, weight, stage of cancer, and other factors specific to the subject to be treated for. 在某些实施方案中,剂量是成人每日约1至约IOOOmg,或成人每日约5至约250mg或每日约10至50mg。 In certain embodiments, the adult daily dose is from about 1 to about IOOOmg, or about 10 to 50mg per day for adults, or from about 5 to about 250mg daily. 在某些实施方案中,剂量是每个成人每日约5至约400mg或每日25至200mg。 In certain embodiments, the dose is 25 to 200mg per adult per day, or from about 5 to about 400mg daily. 在某些实施方案中,还预期每日约50至约500mg的剂量率。 In certain embodiments, also contemplated daily dosage of about 50 to about 500mg of.

[0284] 在其它方面中,提供了治疗或预防受试者的癌症的方法,其通过向有需要的受试者施用有效量的本文提供的化合物或其药学上可接受的盐。 [0284] In other aspects, there is provided a method of treating or preventing cancer in a subject, pharmaceutically provided herein by administering an effective amount of a compound to a subject in need thereof, or a pharmaceutically acceptable salt thereof. 化合物或组合物有效预防或治疗病症或其一种或多种症状的量将随疾病或病状的性质和严重度以及活性成分的施用途径而变。 An amount of a compound or composition effective in preventing or treating a disorder or one or more symptoms of the disease or with the nature and severity of the condition, and the route of administration of the active ingredient becomes. 频率和剂量还将根据每个受试者特定的因素变化,取决于施用的特定疗法(例如治疗剂或预防剂)、病症、疾病或病状的严重度、施用途径以及受试者的年龄、体型、体重、反应和过去病史。 The frequency and dosage will also vary according to factors specific for each subject depending on the particular therapy applied (e.g., therapeutic or prophylactic agents) administered, the severity of the disorder, disease or condition, the route of administration, and the age of the subject, body , body weight, response and past medical history. 可以从来源于体外或动物模型测试系统的剂量反应曲线外推有效剂量。 The reaction may be pushed outside the effective dose from dose curves derived from in vitro or animal model test systems.

[0285] 在某些实施方案中,组合物的示例性剂量包括每公斤受试者或样品重量的活性化合物毫克或微克量(例如每公斤约10微克至每公斤约50毫克、每公斤约100微克至每公斤约25毫克或每公斤约100微克至每公斤约10毫克)。 [0285] In certain embodiments, exemplary dose of the composition include milligram or microgram amounts of the active compound per kilogram of subject or sample weight (e.g., about 10 micrograms per kilogram to about 50 milligrams per kilogram, about 100 kg micrograms to about 25 milligrams per kilogram, or about 100 micrograms per kilogram to about 10 milligrams per kilogram). 对于本文提供的组合物,在某些实施方案中,施用于受试者的剂量是基于活性化合物的重量,每公斤受试者的体重0. HOmg至3mg。 For compositions provided herein, in certain embodiments, the dose administered to the subject is based on the weight of active compound per kilogram body weight of the subject to 0. HOmg 3mg. 在某些实施方案中,施用于受试者的剂量在每公斤受试者的体重0.20mg与2.OOmg之间,或在每公斤受试者的体重0.30mg与1.50mg之间。 In certain embodiments, the dose administered to a subject is between 2.OOmg 0.20mg per kilogram body weight of the subject, or between the subject per kilogram body weight of 0.30mg 1.50mg.

[0286] 在某些实施方案中,针对本文所述的病状,本文提供的组合物的推荐日剂量范围在每日约0. Img至约IOOOmg范围内,以单次一日一次剂量或以一天内分次剂量给与。 [0286] In certain embodiments, the recommended daily dose range of the composition for the conditions described herein, provided herein in a daily dosage of about 0. Img to about IOOOmg range, once daily in a single dose or in one day within a split dose given. 在某些实施方案中,日剂量以同等分次剂量每日施用两次。 In certain embodiments, the daily dose equal divided doses twice daily. 在某些实施方案中,日剂量范围将是每日约IOmg至约200mg,在其它实施方案中,在每日约IOmg与约150mg之间,在其它实施方案中,在每日约25mg与约IOOmg之间。 In certain embodiments, the daily dose range will be from about IOmg day to about 200mg, in other embodiments, between about IOmg day and about 150mg, in other embodiments, the daily dosage of about 25mg and about between IOOmg. 如本领域的一般技术人员所显而易见的,在一些情况下, 可能需要使用在本文公开的范围外的活性成分的剂量。 As those skilled in the art are readily apparent, in some cases, it may require a dose of the active ingredient outside the ranges disclosed herein in use. 此外,注意临床医师或治疗医师将知道结合受试者的反应如何和何时中断、调整或终止疗法。 Also, note that the clinician or treating physician will know how to react combination of subjects and when to interrupt, adjust or terminate therapy.

[0287] 如本领域的一般技术人员所清楚的,不同的治疗有效量可能适用于不同的疾病和病状。 [0287] As those skilled in the art is clear, different therapeutically effective amounts may be applicable for different diseases and conditions. 类似地,本文中描述的剂量和剂量频率时间表还涵盖足够预防、管理、治疗或改善此类病症,但不足以引起或足够减少与本文提供的组合物有关的副作用的量。 Similarly, dose and dose frequency schedule described herein also encompass sufficient to prevent, manage, treat or ameliorate such disorders, but insufficient to cause, or sufficient to reduce the amount relating to the compositions herein provided side effects. 此外,当受试者施用多剂本文提供的组合物时,不是所有的剂量都需要是相同的。 Further, when the subject is administered multiple doses of a composition provided herein, not all of the dosages need be the same. 举例来说,可以增加施用于受试者的剂量以增强组合物的预防或治疗作用,或可以减少剂量以减少特定受试者正经历的一种或多种副作用。 For example, a dose administered to the subject may be increased to enhance for the prophylactic or therapeutic effect of the composition, or the dose may be reduced to reduce the side effects of one or more particular subject is experiencing.

[0288] 在某些实施方案中,基于活性化合物的重量,为预防、治疗、管理或改善受试者的病症或其一种或多种症状而施用的本文提供的组合物的剂量是每公斤受试者的体重0.111^、111^、211^、311^、411^、511^、611^、1〇11^或1511^或更多。 [0288] In certain embodiments, the basis weight of the active compound at a dose of preventing, treating, managing, or ameliorating a disorder or one or more symptoms of the administration of the compositions provided herein is kg the subject's weight 0.111 ^, ^ 111, ^ 211, ^ 311, ^ 411, ^ 511, ^ 611, 1511, or ^ ^ 1〇11 or more. 在另一实施方案中,为预防、治疗、 管理或改善受试者的病症或其一种或多种症状而施用的本文提供的组合物的剂量是〇. Img 至200mg、0·Img至100mg、0·Img至50mg、0·Img至25mg、0·Img至20mg、0·Img至15mg、0·Img至10mg、0·Img至7·5mg、0·Img至5mg、0·1至2·5mg、0·25mg至20mg、0·25至15mg、0·25至12mg、 0·25至10mg、0·25mg至7·5mg、0·25mg至5mg、0·5mg至2·5mg、Img至20mg、Img至15mg、Img至12mg、Img至I Omg、Img至7 · 5mg、Img至5mg 或Img至2 · 5mg 的单位剂量。 In another embodiment, to prevent, treat, manage or ameliorate a disorder or one or more symptoms of the dose administered compositions provided herein are square. Img to 200mg, 0 · Img to 100mg , 0 · Img to 50mg, 0 · Img to 25mg, 0 · Img to 20mg, 0 · Img to 15mg, 0 · Img to 10mg, 0 · Img to 7 · 5mg, 0 · Img to 5mg, 0 · 1 to 2 · 5mg, 0 · 25mg to 20mg, 0 · 25 to 15mg, 0 · 25 to 12mg, 0 · 25 to 10mg, 0 · 25mg to 7 · 5mg, 0 · 25mg to 5mg, 0 · 5mg to 2 · 5mg, Img to 20mg, Img to 15mg, Img to 12mg, Img to I Omg, unit dosage Img to 7 · 5mg, Img to 5mg or to Img of 2 · 5mg.

[0289] 在某些实施方案中,可以用本文提供的化合物或组合物的一种或多种负荷剂量开始治疗或预防,然后是一种或多种维持剂量。 [0289] In certain embodiments, one or more loading dose can be started with the treatment or prevention of a compound provided herein, or combinations thereof, and one or more maintenance doses. 在这类实施方案中,负荷剂量可以是例如每日约60至约400mg或每日约100至约200mg,持续一天至五周。 In such embodiments, the loading dose can be, for example, about 60 to about 400mg per day, or per day from about 100 to about 200mg, continued one day to five weeks. 负荷剂量后面可以是一种或多种维持剂量。 Behind the loading dose may be one or more maintenance doses. 在某些实施方案中,每个维持剂量独立地是每日约IOmg至约200mg,在每日约25mg与约150mg之间,或在每日约25mg与约80mg之间。 In certain embodiments, each maintenance dose independently from about IOmg day to about 200mg, about 25mg daily between between and about 150mg, or about 25mg per day and about 80mg. 维持剂量可以每日施用,并且可以呈单个剂量或呈分次剂量施用。 The daily maintenance dose can be administered, and may be in a single dose or in divided doses.

[0290] 在某些实施方案中,可以施用实现受试者血液或血清中活性成分的稳态浓度的剂量的本文提供的化合物或组合物。 [0290] In certain embodiments, it can be administered to achieve dose of a compound or composition of the subject in the steady state blood or serum concentration of active ingredient provided herein. 稳态浓度可以通过根据技术人员可以利用的技术进行测量来测定,或者可以基于受试者的身体特征,例如身高、体重和年龄。 Steady-state concentration can be determined by measurement according to techniques in the art may be utilized, or may be based on physical characteristics of the subject, such as height, weight and age. 在某些实施方案中,施用足够实现受试者血液或血清中的稳态浓度为约300至约4000ng/mL、约400至约1600ng/mL 或约600至约1200ng/mL的量的本文提供的化合物或组合物。 In certain embodiments, the subject is administered is sufficient to achieve steady-state blood or serum concentrations of about 300 to about 4000ng / mL, an amount of about 400 to about 1600ng / mL or from about 600 to about 1200ng / mL of the herein provided the compound or composition. 在一些实施方案中,可以施用实现约1200至约8000ng/mL或约2000至约4000ng/mL的稳态血液或血清浓度的负荷剂量一天至五天。 In some embodiments, it can be administered to achieve steady-state blood serum concentration or loading dose of about 1200 to about 8000ng / mL or from about 2000 to about 4000ng / mL of one to five days. 在某些实施方案中,可以施用足够实现受试者血液或血清中的稳态浓度为约300 至约4000ng/mL、约400至约1600ng/mL或约600至约1200ng/mL的维持剂量。 In certain embodiments, the subject may be administered to achieve adequate steady-state concentration in blood or serum is from about 300 to about 4000ng / mL, a maintenance dose of about 400 to about 1600ng / mL or from about 600 to about 1200ng / mL of.

[0291] 在某些实施方案中,相同组合物的施用可以重复进行并且施用可以相隔至少1天、 2天、3天、5天、10天、15天、30天、45天、2个月、75天、3个月或6个月。 [0291] In certain embodiments, administration of the same composition may be repeated and the administration may be separated by at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months , 75 days, three months or six months. 在其它实施方案中,相同预防剂或治疗剂的施用可以重复进行并且施用可以相隔至少1天、2天、3天、5天、10天、15 天、30天、45天、2个月、75天、3个月或6个月。 In other embodiments, administration of the same prophylactic or therapeutic agent may be repeated and the administration may be separated by at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, three months or six months.

[0292] 在某些方面中,本文提供了呈适合于施用的形式的包含化合物或其药学上可接受的盐的单位剂量。 [0292] In certain aspects, provided herein are unit dosages comprising a compound or a pharmaceutically acceptable salt thereof in a form suitable for administration form. 本文中详细描述此类形式。 Such forms are described in detail herein. 在某些实施方案中,单位剂量包含1至l〇〇〇mg、 5至250mg或10至50mg活性成分。 In certain embodiments, the unit dosage comprises 1 to l〇〇〇mg, 5 to 250mg or 10 to 50mg active ingredient. 在具体实施方案中,单位剂量包含约1、5、10、25、50、100、 125、250、500或IOOOmg活性成分。 In a particular embodiment, the unit dose contains about 1,5,10,25,50,100, 125, 250, or the active ingredient IOOOmg. 此类单位剂量可以根据本领域的技术人员熟悉的技术来制备。 Such unit doses may be prepared according to art in the art are familiar with the art.

[0293] 一定剂量的第二药剂将用于本文提供的组合疗法中。 Second agent [0293] The dose for the combination therapy provided herein. 在某些实施方案中,低于已经或当前正用于预防或治疗癌症的剂量的剂量用于本文提供的组合疗法中。 In certain embodiments, a dose lower than has been or is currently being used for preventing or treating cancer in a dose for the combination therapy provided herein. 技术人员知晓第二药剂的推荐剂量。 Art is aware of the recommended dose of the second medicament. 关于经批准用于临床使用的那些第二药剂,推荐剂量描述于例如Hardman等人编,1996,Goodman&Gilman' s The Pharmacological Basis Of Basis Of Therapeutics第9版,Mc-Graw-Hill,New York;PhYsician's Desk Reference (PDR)第57 版·,2003,Medical Economics Co.,Inc.,Montvale,NJ;这些文献以引用的方式整体并入本文中。 About those second agent approved for clinical use, recommended dosages are described in, for example, Hardman et al, eds, 1996, Goodman & amp; Gilman 's The Pharmacological Basis Of Basis Of Therapeutics Edition 9, Mc-Graw-Hill, New York; PhYsician's Desk reference (PDR) 57th Edition ·, 2003, Medical Economics Co., Inc., Montvale, NJ; these documents incorporated herein by reference.

[0294] 在多个实施方案中,所述疗法(例如本文提供的化合物和第二药剂)相隔不到5分钟、相隔不到30分钟、相隔1小时、相隔约1小时、相隔约1至约2小时、相隔约2小时至约3小时、相隔约3小时至约4小时、相隔约4小时至约5小时、相隔约5小时至约6小时、相隔约6小时至约7小时、相隔约7小时至约8小时、相隔约8小时至约9小时、相隔约9小时至约10小时、相隔约10小时至约11小时、相隔约11小时至约12小时、相隔约12小时至18小时、相隔18小时至24小时、相隔24小时至36小时、相隔36小时至48小时、相隔48小时至52小时、相隔52小时至60小时、相隔60小时至72小时、相隔72小时至84小时、相隔84小时至96小时或相隔96小时至120小时施用。 [0294] In various embodiments, the therapies (e.g., a compound provided herein and the second agent) less than 5 minutes apart, less than 30 minutes apart, 1 hour apart, separated by about 1 hour apart, at about 1 to about 2 hours apart, at about 2 hours to about 3 hours apart, at about 3 hours to about 4 hours apart, at about 4 hours to about 5 hours apart, at about 5 hours to about 6 hours apart, at about 6 hours to about 7 hours apart, at about 7 hours to about 8 hours apart, at about 8 hours to about 9 hours apart, at about 9 hours to about 10 hours apart, at about 10 hours to about 11 hours apart, at about 11 hours to about 12 hours apart, at about 12 to 18 hours , separated by 18 to 24 hours apart, 24 to 36 hours apart, 36 to 48 hours apart, 48 to 52 hours apart, 52 to 60 hours apart, 60 to 72 hours apart, 72 to 84 hours, separated by 84 to 96 hours apart, or 96 to 120 hours of administration. 在多个实施方案中,所述疗法相隔至多24小时或相隔至多48小时施用。 In various embodiments, the therapy is spaced apart up to up to 24 hours or 48 hours after administration. 在某些实施方案中,两种或更多种疗法在同一次患者就诊期间施用。 In certain embodiments, two or more therapies administered during the same patient visit. 在其它实施方案中,本文提供的化合物和第二药剂同时施用。 In other embodiments, the compound provided herein and the second agent are administered simultaneously.

[0295] 在其它实施方案中,本文提供的化合物和第二药剂相隔约2至4天、相隔约4至6天、 相隔约1周、相隔约1至2周或相隔超过2周施用。 [0295] In other embodiments, the compound provided herein and the second agent are spaced apart from about 2 to 4 days apart, at about 4 to 6 days apart, at about 1 week apart, at about 1 to 2 weeks apart, or more than 2 weeks of administration.

[0296] 在某些实施方案中,相同药剂的施用可以重复进行并且施用可以相隔至少1天、2 天、3天、5天、10天、15天、30天、45天、2个月、75天、3个月或6个月。 [0296] In certain embodiments, administration of the same agent may be repeated and the administration may be separated by at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, three months or six months. 在其它实施方案中,相同药剂的施用可以重复进行并且施用可以相隔至少1天、2天、3天、5天、10天、15天、30天、45 天、2个月、75天、3个月或6个月。 In other embodiments, administration of the same agent may be repeated and the administration may be separated by at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months or six months.

[0297] 在某些实施方案中,本文提供的化合物和第二药剂以一定顺序和在一定时间间隔内施用于患者,例如哺乳动物,例如人类,以使本文提供的化合物可以与另一药剂一起起作用,从而使得益处比其以其它方式施用时增加。 [0297] In certain embodiments, the compound provided herein and the second agent is in a sequence and within a time interval administered to a patient, such as mammals, for example humans, such that the compound provided herein together with another agent may be function, so that an increased benefit than when it is administered in other ways. 举例来说,第二活性剂可以同时施用,或在不同的时间点以任何次序依序施用;但是,如果不同时施用,那么其将在足够靠近的时间施用以便提供所需治疗或预防作用。 For example, the second active agent can be administered simultaneously, or administered sequentially in any order at different points in time; however, if not administered simultaneously, then it will be administered to provide the desired therapeutic or prophylactic effect in the time close enough. 在某些实施方案中,本文提供的化合物和第二活性剂有时发挥重叠的作用。 In certain embodiments, a compound provided herein and a second active agent may exert overlapping roles. 每种第二活性剂可以分开、呈任何适当的形式和通过任何合适的途径施用。 Each second active agent can be separated in any appropriate form and by any suitable route of administration. 在其它实施方案中,本文提供的化合物在第二活性剂施用之前、同时或之后施用。 In other embodiments, compounds provided herein are administered prior to a second active agent, concurrently or after administration.

[0298] 在某些实施方案中,本文提供的化合物和第二药剂循环施用于患者。 [0298] In certain embodiments, the compound provided herein and the second agent is administered to a patient loop. 循环疗法包括施用第一药剂(例如第一预防或治疗剂)一段时间,然后施用第二药剂和/或第三药剂(例如第二和/或第三预防或治疗剂)一段时间,并且重复此依序施用。 Cycling therapy involves the administration of a first agent (e.g., a first prophylactic or therapeutic agent) for a period of time, and then administering a second agent and / or third agent (e.g., a second and / or third prophylactic or therapeutic agents) for a period of time, and repeating this sequential administration. 循环疗法可以减少对所述疗法中的一种或多种疗法的抗性的发展,避免或减少所述疗法中的一种疗法的副作用和/或提尚治疗的功效。 Cycling therapy can reduce the development of resistance to one or more of the therapies therapies, avoid or reduce the side effects of one of the therapies efficacy of the therapy and / or provide therapy yet.

[0299] 在某些实施方案中,本文提供的化合物和第二活性剂以少于约3周、每两周大约一次、每10天大约一次或每周大约一次的周期施用。 [0299] In certain embodiments, a compound provided herein and a second active agent of less than about 3 weeks, about once every two weeks, about once every 10 days or about once a cycle is administered weekly. 一个周期可以包括本文提供的化合物和第二药剂通过每个周期输液约90分钟、每个周期输液约1小时、每个周期输液约45分钟来施用。 Cycle may comprise a compound provided herein and the second agent by infusion of about 90 minutes every cycle, about 1 hour infusion every cycle, about 45 minutes every cycle infusion administered. 每个周期可以包含至少1周停止、至少2周停止、至少3周停止。 Each cycle can comprise at least 1 week stopped, stopped at least 2 weeks, at least 3 weeks stopped. 施用的周期数目是约1至约12个周期,更典型地约2至约10个周期,且更典型地约2至约8个周期。 The number of cycles administered is from about 1 to about 12 cycles, more typically from about 2 to about 10 cycles, and more typically from about 2 to about 8 cycles.

[0300] 在其它实施方案中,治疗过程同时施用于患者,即第二药剂的个别剂量分开但在一次时间间隔内施用,以使本文提供的化合物可以与第二活性剂一起起作用。 [0300] In other embodiments, the course of treatment administered to a patient simultaneously, i.e., individual doses of the second agent is administered separately but within a time interval such that the compound provided herein can work together with the second active agent. 举例来说,一种组分可以与其它组分组合每周施用一次,其它组分可以每两周施用一次或每三周施用一次。 For example, one component can be administered once a week in combination with other components, other components may be administered once every two weeks or once every three weeks. 换句话说,即使治疗剂不同时或在同一天内施用,给药方案也是同时进行的。 In other words, even if the therapeutic agent is not administered simultaneously or on the same day, the dosage regimen is carried out simultaneously.

[0301] 第二药剂可以与本文提供的化合物累加或协同作用。 [0301] The second agent may be the compound provided herein is additive or synergistic effect. 在某些实施方案中,本文提供的化合物与一种或多种第二药剂在同一药物组合物中同时施用。 In certain embodiments, a compound with one or more second agents provided herein is administered concurrently in the same pharmaceutical composition. 在另一实施方案中,本文提供的化合物与一种或多种第二药剂在分开的药物组合物中同时施用。 In another embodiment, a compound with one or more second agents provided herein are administered simultaneously in separate pharmaceutical compositions. 在又一实施方案中,本文提供的化合物在第二药剂施用之前或之后施用。 In yet another embodiment, the compound provided herein is administered before or after administration of the second agent. 还预期本文提供的化合物和第二药剂通过相同或不同的施用途径,例如经口和肠胃外来施用。 Also contemplated compound provided herein and the second agent by the same or different routes of administration, such as oral and parenteral administration foreign. 在某些实施方案中,当本文提供的化合物与可能产生包括(但不限于)毒性在内的不良副作用的第二药剂同时施用时,第二活性剂宜以低于引起不良副作用的阈值的剂量施用。 In certain embodiments, when the compound provided herein and the second agent may occur include (but are not limited to) the adverse side effects including toxicity administered simultaneously, the second active agent should be below the dose threshold to cause adverse side effects administration.

[0302] 试剂盒 [0302] Kit

[0303] 还提供了用于治疗癌症,例如肝癌,例如肝细胞癌、胆管细胞型肝癌或胆道癌的方法中的试剂盒。 [0303] Also provided for treating cancer, such as liver cancer, for example hepatocellular carcinoma, cholangiocarcinoma or bile duct cancer process kit. 在某些实施方案中,癌症选自乳腺癌、卵巢癌、肺癌、胰腺癌或白血病癌。 In certain embodiments, the cancer is selected from breast cancer, ovarian cancer, lung cancer, pancreatic cancer or leukemia. 试剂盒可以包括本文提供的化合物或组合物、第二药剂或组合物和为保健提供者提供关于治疗病症的用法的信息的说明书。 The kit may comprise a compound provided herein or composition, a second agent or composition, and to provide instructions to a healthcare provider information about the usage of the condition being treated. 说明书可以呈印刷形式,或呈例如软盘、CD或DVD等电子媒体形式,或呈可以获得此类说明书的网站地址的形式提供。 Instructions may be in printed form, or in the form of electronic media such as floppy disks, CD or DVD, or in the form of providing such a description may be obtained site addresses. 本文提供的化合物或组合物或第二药剂或组合物的单位剂量可以包括在施用于受试者时,可以维持受试者体内化合物或组合物的治疗或预防有效血浆水平至少1天的剂量。 Provided herein a unit dose of a compound or a composition or a second agent or composition may include when administered to a subject, maintenance therapy may be subject compound or composition or prophylactically effective plasma level of at least 1 day dose. 在一些实施方案中,化合物或组合物可以呈无菌水性药物组合物或干粉(例如冻干)组合物形式包括。 In some embodiments, the compound or composition may be in a sterile aqueous pharmaceutical composition or dry powder (e.g., lyophilized) form comprises a composition.

[0304] 在一些实施方案中,提供合适的包装。 [0304] In some embodiments, suitable packaging provided. 如本文所用,“包装”包括通常用于系统中并能够将适合施用于受试者的本文提供的化合物和/或第二药剂保持在固定限制内的固体基质或材料。 As used herein, "packaging" normally used in the system and can be applied to a suitable compound and / or the second agent provided herein, the subject of holding within fixed limits a solid matrix or material. 此类材料包括玻璃和塑料(例如聚乙烯、聚丙烯和聚碳酸酯)瓶、小瓶、纸、塑料和塑料箱层压的封套等等。 Such materials include glass and plastic (e.g., polyethylene, polypropylene and polycarbonate) bottles, vials, paper, plastic, and plastic boxes laminated envelopes and the like. 如果采用电子束灭菌技术,那么包装将具有足够低密度以允许将内含物灭菌。 If e-beam sterilization techniques are employed, then the package will have a sufficient density to permit sterilization of the contents.

[0305] 使用方法 [0305] Use

[0306] 在一个实施方案中,是一种化合物或其药学上可接受的盐、溶剂化物、立体异构形式、互变异构形式或多晶型物。 [0306] In one embodiment, a compound or a pharmaceutically acceptable salt thereof, solvate thereof, stereoisomeric forms, tautomeric forms or polymorphs.

[0307] 本文提供了一种用于治疗受试者的癌症的方法,其包括使受试者与治疗有效量的本文公开的核苷酸类似物接触,所述核苷酸类似物例如式I-VIII的化合物,包括其单一对映异构体、对映异构体对的混合物、个别非对映异构体、非对映异构体的混合物或互变异构形式;或其药学上可接受的盐、溶剂化物、前药、磷酸盐或活性代谢物。 [0307] Provided herein is a method for treating cancer in a subject comprising contacting the subject with a therapeutically effective amount of a nucleotide analogs disclosed herein contacting said nucleotide analogues of formula I e.g. -VIII compounds, including single enantiomers, enantiomeric mixtures of the individual diastereomers, mixtures of diastereomers thereof, or tautomeric form; or a pharmaceutically acceptable salt, solvate, prodrug, active metabolite, or phosphate. 在某些实施方案中, 癌症选自肝癌、乳腺癌、卵巢癌、肺癌、胰腺癌或白血病癌。 In certain embodiments, the cancer is selected from cancer, breast cancer, ovarian cancer, lung cancer, pancreatic cancer or leukemia. 在一个实施方案中,癌症是肝癌。 In one embodiment, the cancer is liver cancer. 可以治疗的肝癌包括原发性肝癌和继发性肝癌。 Liver cancer may include the treatment of primary liver cancer and secondary liver cancer. 在具体实施方案中,肝癌是肝细胞癌、胆管细胞型肝癌或胆道癌。 In a particular embodiment, the liver cancer is hepatocellular carcinoma, cholangiocarcinoma or bile duct cancer. 在具体实施方案中,肝癌是肝中起源于其它癌症(例如结肠癌、胰腺癌等)的癌转移。 In a particular embodiment, the liver is the liver originated in other cancers (such as colon, pancreatic, etc.) cancer metastasis.

[0308] 本文提供了一种用于抑制癌细胞生长的方法,其包括使细胞与治疗有效量的本文公开的化合物接触,所述化合物例如式I-VIII的化合物,包括其单一对映异构体、对映异构体对的混合物、个别非对映异构体、非对映异构体的混合物或互变异构形式;或其药学上可接受的盐、溶剂化物、前药、磷酸盐或活性代谢物。 [0308] Provided herein are single enantiomer thereof A method for inhibiting the growth of cancer cells, comprising contacting the cell with a compound of a therapeutically effective amount of the herein disclosed, for example, a compound of formula I-VIII of the compound, comprising thereof, mixtures of enantiomers, individual diastereomers, mixtures of diastereomeric isomers or tautomeric form; or a pharmaceutically acceptable salt, solvate, prodrug, acid active metabolite or salt thereof. 在某些实施方案中,癌症选自肝癌、乳腺癌、卵巢癌、肺癌、胰腺癌或白血病癌。 In certain embodiments, the cancer is selected from cancer, breast cancer, ovarian cancer, lung cancer, pancreatic cancer or leukemia. 在一个实施方案中,癌症是肝癌。 In one embodiment, the cancer is liver cancer. 在某些实施方案中, 肝癌是肝细胞癌、胆管细胞型肝癌或胆道癌。 In certain embodiments, the liver cancer is hepatocellular carcinoma, cholangiocarcinoma or bile duct cancer. 在具体实施方案中,癌症是肝细胞癌。 In a specific embodiment, the cancer is hepatocellular carcinoma.

[0309] 本文提供了一种用于抑制癌细胞复制的方法,其包括使细胞与治疗有效量的本文公开的化合物接触,所述化合物例如式I-VIII的化合物,包括其单一对映异构体、对映异构体对的混合物、个别非对映异构体、非对映异构体的混合物或互变异构形式;或其药学上可接受的盐、溶剂化物、前药、磷酸盐或活性代谢物。 [0309] Provided herein is a method for inhibiting replication of cancer cells, comprising contacting the cell with a compound of a therapeutically effective amount of the herein disclosed, for example, the compounds of formula I-VIII compounds, including a single enantiomer thereof, mixtures of enantiomers, individual diastereomers, mixtures of diastereomeric isomers or tautomeric form; or a pharmaceutically acceptable salt, solvate, prodrug, acid active metabolite or salt thereof. 在某些实施方案中,癌症选自肝癌、乳腺癌、卵巢癌、肺癌、胰腺癌或白血病癌。 In certain embodiments, the cancer is selected from cancer, breast cancer, ovarian cancer, lung cancer, pancreatic cancer or leukemia. 在一个实施方案中,癌症是肝癌。 In one embodiment, the cancer is liver cancer. 在某些实施方案中, 肝癌是肝细胞癌、胆管细胞型肝癌或胆道癌。 In certain embodiments, the liver cancer is hepatocellular carcinoma, cholangiocarcinoma or bile duct cancer. 在具体实施方案中,癌症是肝细胞癌。 In a specific embodiment, the cancer is hepatocellular carcinoma.

[0310] 本文提供了一种用于抑制肿瘤生长的方法,其包括使肿瘤与本文公开的化合物接触,所述化合物例如式I-VIII的化合物,包括其单一对映异构体、对映异构体对的混合物、 个别非对映异构体、非对映异构体的混合物或互变异构形式;或其药学上可接受的盐、溶剂化物、前药、磷酸盐或活性代谢物。 [0310] Provided herein is a method for inhibiting tumor growth, comprising contacting the tumor with a compound disclosed herein, e.g. a compound of formula I-VIII of the compound, including its single enantiomers, enantiomerically iso the mixture of isomers, and individual diastereomers thereof, diastereomers thereof or of a mixture of tautomeric forms; or a pharmaceutically acceptable salt, solvate, prodrug, active metabolite, or a phosphate . 在某些实施方案中,肿瘤选自肝部肿瘤、胸部肿瘤、卵巢肿瘤、肺部肿瘤、胰腺肿瘤或白血病肿瘤。 In certain embodiments, the tumor is selected from liver tumor, breast cancer, ovarian cancer, lung cancer, pancreas cancer or leukemia. 在一个实施方案中,肿瘤是肝部肿瘤。 In one embodiment, the tumor is a liver cancer. 在某些实施方案中,肝部肿瘤是肝细胞癌、胆管细胞型肝癌或胆道癌。 In certain embodiments, the liver cancer is hepatocellular carcinoma, cholangiocarcinoma or bile duct cancer. 在具体实施方案中,肿瘤是肝细胞癌。 In a specific embodiment, the tumor is hepatocellular carcinoma.

[0311] 在某些实施方案中,本文提供了用于治疗和/或预防受试者的癌症的方法,其包括施用有效量的本文公开的核苷化合物,所述核苷化合物例如式I-VIII的核苷化合物,包括其单一对映异构体、对映异构体对的混合物、个别非对映异构体、非对映异构体的混合物或互变异构形式;或其药学上可接受的盐、溶剂化物、前药、磷酸盐或活性代谢物。 [0311] In certain embodiments, it provided herein and / or prevention methods for treating cancer in a subject, comprising administering an effective amount of a nucleoside compound disclosed herein, for example the nucleoside compound of formula I- nucleosides VIII compounds, including single enantiomers, mixtures of enantiomers, individual diastereomers thereof, diastereomers thereof or of a mixture of tautomeric forms; or a pharmaceutically acceptable acceptable salt, solvate, prodrug, active metabolite, or phosphate. 在某些实施方案中,癌症选自肝癌、乳腺癌、卵巢癌、肺癌、胰腺癌或白血病癌。 In certain embodiments, the cancer is selected from cancer, breast cancer, ovarian cancer, lung cancer, pancreatic cancer or leukemia. 在一个实施方案中,癌症是肝癌。 In one embodiment, the cancer is liver cancer. 在某些实施方案中,肝癌是肝细胞癌、胆管细胞型肝癌或胆道癌。 In certain embodiments, the liver cancer is hepatocellular carcinoma, cholangiocarcinoma or bile duct cancer. 在具体实施方案中,癌症是肝细胞癌。 In a specific embodiment, the cancer is hepatocellular carcinoma.

[0312] 在某些实施方案中,本文提供了用于治疗受试者的癌症的方法。 [0312] In certain embodiments, provided herein are methods for treating cancer in a subject. 在某些实施方案中,所述方法涵盖向有需要的受试者施用有效治疗或预防癌症的量的化合物与有效治疗或预防癌症的第二药剂组合的步骤。 In certain embodiments, the methods encompass the step amount effective for treating or preventing cancer compound and the second agent effective for treating or preventing cancer in combination administering to a subject in need thereof. 化合物可以是如本文所述的任何化合物,并且第二药剂可以是本领域或本文中描述的任何第二药剂。 Compound may be any compound as described herein and the second agent can be any second agent in the art or described herein. 在某些实施方案中,化合物呈药物组合物或剂型形式,如本文中其它地方所述。 In certain embodiments, the compound as a pharmaceutical composition or dosage form, as described elsewhere herein. 在某些实施方案中,癌症选自肝癌、乳腺癌、卵巢癌、肺癌、胰腺癌或白血病癌。 In certain embodiments, the cancer is selected from cancer, breast cancer, ovarian cancer, lung cancer, pancreatic cancer or leukemia. 在一个实施方案中,癌症是肝癌。 In one embodiment, the cancer is liver cancer. 在某些实施方案中,肝癌是肝细胞癌、胆管细胞型肝癌或胆道癌。 In certain embodiments, the liver cancer is hepatocellular carcinoma, cholangiocarcinoma or bile duct cancer. 在具体实施方案中,癌症是肝细胞癌。 In a specific embodiment, the cancer is hepatocellular carcinoma.

[0313] 在某些实施方案中,本文提供了用于治疗和/或预防受试者的癌症的方法,其包括施用有效量的本文提供的化合物或其药学上可接受的盐。 [0313] In certain embodiments, provided herein are methods for the treatment and / or prevention of cancer in a subject, comprising administering a pharmaceutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof. 在某些实施方案中,本文提供了用于治疗受试者的癌症的方法。 In certain embodiments, provided herein are methods for treating cancer in a subject. 在某些实施方案中,所述方法涵盖向有需要的受试者施用有效治疗或预防癌症的量的化合物与有效治疗或预防肝癌的第二药剂组合的步骤。 In certain embodiments, the methods encompass the step of administering an amount effective for treating or preventing cancer in a subject in need of the compound and the second agent effective to treat or prevent liver cancer combined. 化合物可以是如本文所述的任何化合物,并且第二药剂可以是本领域或本文中描述的任何第二药剂。 Compound may be any compound as described herein and the second agent can be any second agent in the art or described herein. 在某些实施方案中,化合物呈药物组合物或剂型形式,如本文中其它地方所述。 In certain embodiments, the compound as a pharmaceutical composition or dosage form, as described elsewhere herein. 在某些实施方案中,癌症选自肝癌、乳腺癌、卵巢癌、肺癌、胰腺癌或白血病癌。 In certain embodiments, the cancer is selected from cancer, breast cancer, ovarian cancer, lung cancer, pancreatic cancer or leukemia. 在一个实施方案中, 癌症是肝癌。 In one embodiment, the cancer is liver cancer. 在某些实施方案中,肝癌是肝细胞癌、胆管细胞型肝癌或胆道癌。 In certain embodiments, the liver cancer is hepatocellular carcinoma, cholangiocarcinoma or bile duct cancer. 在具体实施方案中,癌症是肝细胞癌。 In a specific embodiment, the cancer is hepatocellular carcinoma.

[0314] 在一个实施方案中,可以用本文所述的化合物治疗的癌症包括(但不限于)急性淋巴母细胞性白血病;急性骨髓性白血病;肾上腺皮质癌;艾滋病相关性淋巴瘤;艾滋病相关性恶性病;肛门癌;星形细胞瘤;胆管癌;膀胱癌;骨癌、骨肉瘤/恶性纤维组织细胞瘤;脑干胶质瘤;脑肿瘤,小脑星形细胞瘤;脑肿瘤,大脑星形细胞瘤/恶性胶质瘤;脑肿瘤,室管膜瘤;脑肿瘤,成神经管细胞瘤;脑肿瘤,幕上原始神经外胚瘤;脑肿瘤,视通路和下丘脑胶质瘤;乳腺癌;支气管腺瘤/类癌瘤;类癌肿瘤;胃肠道类癌;肾上腺皮质癌;胰岛细胞癌;原发性中枢神经系统淋巴瘤;大脑星形细胞瘤/恶性胶质瘤;子宫颈癌;慢性淋巴细胞性白血病; 慢性髓细胞性白血病;慢性骨髓增生性病症;腱鞘透明细胞肉瘤;结肠癌;结肠直肠癌;皮肤T细胞淋巴瘤;子宫内膜癌;室管膜瘤;卵巢上皮癌;食道癌;食道癌; [0314] In one embodiment, the cancer may be treated by compounds described herein include (but are not limited to) acute lymphoblastic leukemia; acute myeloid leukemia; adrenocortical carcinoma; AIDS-related lymphoma; AIDS associated malignancies; anal carcinoma; astrocytoma; cholangiocarcinoma; bladder cancer; bone cancer, osteosarcoma / malignant fibrous histiocytoma; brain stem glioma; brain tumor, cerebellar astrocytoma; brain tumor, cerebral astrocytoma tumor / malignant glioma; brain tumor, ependymoma; brain tumor, medulloblastoma; brain tumor, supratentorial primitive neuroectodermal tumor; brain tumor, visual pathway and hypothalamic glioma; breast cancer ; bronchial adenoma / carcinoid tumor; carcinoid tumor; gastrointestinal carcinoid; adrenocortical carcinoma; islet cell carcinoma; primary central nervous system lymphoma; cerebral astrocytoma / glioblastoma; cervical cancer ; chronic lymphocytic leukemia; chronic myelogenous leukemia; chronic myeloproliferative disorders; sheath clear cell sarcoma; colon; of colorectal cancer; cutaneous T cell lymphoma; endometrial cancer; ependymoma; epithelial ovarian cancer ; esophageal cancer; esophageal cancer; 尤因家族肿瘤(Ewing/ s Family of Tumor);颅外生殖细胞肿瘤;肝外胆管癌;眼癌,眼内黑色素瘤;眼癌,成视网膜细胞瘤;胆囊癌;胃(胃)癌;胃肠道类癌;儿童颅外生殖细胞肿瘤;性腺外生殖细胞肿瘤;卵巢生殖细胞肿瘤;妊娠滋养细胞瘤;儿童脑干胶质瘤;儿童视通路和下丘脑胶质瘤;毛细胞白血病;头颈部癌;肝细胞(肝)癌;霍奇金淋巴瘤(Hodgkir/s Lymphoma);下咽癌;下丘脑和视通路胶质瘤;眼内黑色素瘤;胰岛细胞癌(内分泌胰腺);卡波西肉瘤(Kaposi、 Sarcoma);肾癌;喉癌;急性淋巴母细胞性白血病;急性脊髓性白血病;慢性淋巴细胞性白血病;慢性髓细胞性白血病;毛细胞白血病;唇和口腔癌;肝癌;非小细胞肺癌;小细胞肺癌;淋巴母细胞性白血病;艾滋病相关性淋巴瘤;中枢神经系统(原发性)淋巴瘤;皮肤T细胞淋巴瘤;霍奇金淋巴瘤;妊娠期霍奇金淋巴瘤;非霍奇金淋巴瘤;原发性 Ewing's family of tumors (Ewing / s Family of Tumor); extracranial germ cell tumor; cholangiocarcinoma; retinoblastoma, intraocular melanoma; eye cancer, retinoblastoma; gallbladder carcinoma; gastric (stomach) cancer; stomach intestinal carcinoid; children extracranial germ cell tumor; extragonadal germ cell tumors; ovarian germ cell tumor; gestational trophoblastic tumor; child brain stem glioma; child visual pathway and hypothalamic glioma; hairy cell leukemia; head neck cancer; hepatocellular (liver) carcinoma; Hodgkin's lymphoma (Hodgkir / s lymphoma); hypopharyngeal; hypothalamic and visual pathway glioma; intraocular melanoma; islet cell carcinoma (endocrine pancreas); card Posey sarcoma (Kaposi, sarcoma); kidney; laryngeal; acute lymphoblastic leukemia; acute spinal leukemia; chronic lymphocytic leukemia; chronic myelogenous leukemia; hairy cell leukemia; lip and oral cavity cancer; liver cancer; non-small cell lung cancer; small cell lung cancer; lymphoblastic leukemia; AIDS-related lymphoma; Central Nervous system (primary) lymphoma; cutaneous T cell lymphomas; Hodgkin's lymphoma; Hodgkin pregnancy tumors; non-Hodgkin's lymphoma; primary 中枢神经系统淋巴瘤;瓦尔登斯特伦氏巨球蛋白血症(Waldenstron/s Macroglobulinemia);男性乳腺癌;恶性间皮瘤;恶性胸腺瘤;儿童髓母细胞瘤;黑色素瘤;眼内黑色素瘤;默克尔细胞癌(Merkel Cel 1 Carcinoma);恶性间皮瘤;伴有隐匿性原发灶的转移性鳞状颈癌;儿童多发性内分泌腺瘤综合征;多发性骨髓瘤/浆细胞肿瘤;蕈样真菌病;骨髓增生异常综合征;慢性髓细胞性白血病;骨髓性白血病;多发性骨髓瘤;慢性骨髓增生性病症;鼻腔和鼻窦癌;鼻咽癌;神经母细胞瘤;非霍奇金淋巴瘤;非小细胞肺癌;□腔癌;□腔与唇癌;□咽癌;骨肉瘤/骨恶性纤维组织细胞瘤;卵巢上皮癌;卵巢生殖细胞肿瘤;卵巢低度恶性潜能肿瘤;胰腺癌;鼻窦和鼻腔癌;甲状旁腺癌;阴茎癌;嗜铬细胞瘤;松果体和幕上原始神经外胚瘤;垂体瘤;浆细胞肿瘤/ 多发性骨髓瘤;胸膜肺母细胞瘤;妊娠期乳腺癌;妊娠 Central nervous system lymphoma; Waldenstrom's macroglobulinemia (Waldenstron / s Macroglobulinemia); male breast cancer; malignant mesothelioma; malignant thymoma; children with medulloblastoma; melanoma; intraocular melanoma ; Merkel cell carcinoma (Merkel Cel 1 carcinoma); malignant mesothelioma; metastatic squamous neck cancer with occult primary lesion; child multiple endocrine neoplasia syndrome; multiple myeloma / plasma cell neoplasms ; mycosis fungoides; myelodysplastic syndrome; chronic myelogenous leukemia; myeloid leukemia; multiple myeloma; chronic myeloproliferative disorders; nasal and paranasal sinus cancer; nasopharyngeal; neuroblastoma; non-Hodgkin lymphoma; non-small cell lung cancer; □ cavity cancer; □ cavity and lip cancer; □ pharynx; osteosarcoma / malignant fibrous histiocytoma of bone; epithelial ovarian cancer; ovarian germ cell tumor; ovarian low malignant potential tumor; pancreas cancer; and nasal sinus cancer; parathyroid cancer; penile carcinoma; pheochromocytoma; the pineal and supratentorial primitive neuroectodermal tumor; pituitary tumor; plasma cell neoplasm / multiple myeloma; pleuropulmonary blastoma; breast cancer during pregnancy; pregnancy 期霍奇金淋巴瘤;妊娠期非霍奇金淋巴瘤;原发性中枢神经系统淋巴瘤;原发性肝癌;前列腺癌;直肠癌;肾细胞(肾)癌;肾盂和输尿管移行细胞癌;视网膜母细胞瘤;横纹肌肉瘤;唾液腺癌;尤因家族肿瘤肉瘤;卡波西肉瘤;肉瘤(骨肉瘤)/骨恶性纤维组织细胞瘤;软组织肉瘤;塞扎莱综合征(Sezary Syndrome);皮肤癌;皮肤癌(黑色素瘤);默克尔细胞皮肤癌;小细胞肺癌;小肠癌;软组织肉瘤;伴有隐匿性原发灶的转移性鳞状颈癌;胃(胃)癌;幕上原始神经外胚瘤;皮肤T细胞淋巴瘤;睾丸癌;恶性胸腺瘤;甲状腺癌;肾盂和输尿管移行细胞癌;妊娠滋养细胞肿瘤;输尿管和肾盂移行细胞癌;尿道癌;子宫肉瘤;阴道癌;视通路和下丘脑胶质瘤;外阴癌;瓦尔登斯特伦氏巨球蛋白血症;和韦尔姆斯氏瘤(WilmsIumor)。 Hodgkin's lymphoma; pregnancy non-Hodgkin's lymphoma; primary central nervous system lymphoma; primary liver cancer; prostate cancer; colorectal cancer; renal cell (kidney) cancer; renal pelvis and ureter transitional cell carcinoma; retinoblastoma; rhabdomyosarcoma; salivary gland; Ewing's sarcoma family of tumors; Kaposi's sarcoma; s sarcoma (osteosarcoma) / malignant fibrous histiocytoma of bone; soft tissue sarcoma; Se Zhalai syndrome (Sezary syndrome); skin cancer ; skin cancer (melanoma); Merkel cell skin cancer; small cell lung cancer; small intestine; soft tissue sarcoma; with occult primary tumor metastatic squamous neck cancer; gastric (stomach) cancer; curtain on raw nerve ectodermal tumor; cutaneous T cell lymphoma; testicular cancer; malignant thymoma; thyroid cancer; carcinoma of the renal pelvis and ureter transitional cell; gestational trophoblastic tumor; transitional cell carcinoma of the renal pelvis and ureter; urinary tract cancer; uterine sarcoma; vaginal cancer; visual pathway and hypothalamic glioma; vulvar cancer; Waldenstrom's macroglobulinemia; and Wilms' tumor (WilmsIumor).

[0315] 在一个实施方案中,可能与突变IDH酶活性有关的癌症是脑癌,例如星形细胞肿瘤(例如纤维性星形细胞瘤、室管膜下巨细胞型星形细胞瘤、弥漫性星形细胞瘤、多形性黄色星形细胞瘤、间变性星形细胞瘤、星形细胞瘤、巨细胞型胶质母细胞瘤、胶质母细胞瘤、继发性胶质母细胞瘤、成人原发性胶质母细胞瘤和儿童原发性胶质母细胞瘤);少突胶质细胞肿瘤(例如少突胶质瘤和间变性少突胶质瘤);少突星形细胞肿瘤(例如少突星形细胞瘤和间变性少突星形细胞瘤);室管膜瘤(例如粘液乳头型室管膜瘤和间变性室管膜瘤);髓母细胞瘤;原始神经外胚层瘤、许旺细胞瘤(schwannoma)、脑膜瘤、非典型脑膜瘤(meatypical meningioma)、间变性脑膜瘤;和垂体腺瘤。 [0315] In one embodiment, the mutation may IDH activity is brain cancer, for example, astrocytic tumors (e.g. fibrous astrocytoma, giant cell subependymal astrocytoma, diffuse astrocytoma, pleomorphic yellow astrocytoma, anaplastic astrocytoma, astrocytoma, giant cell glioblastoma, glioblastoma, secondary glioblastoma, adult primary glioblastoma and in children with primary glioblastoma); oligodendroglial tumors (e.g. oligodendroglioma and anaplastic oligodendroglioma); oligodendrocytes astrocytomas (e.g., oligodendrocytes and astrocytoma anaplastic astrocytoma oligodendrocytes); ependymoma (e.g., papillary mucinous ependymoma and anaplastic ependymoma); medulloblastoma; primitive neuroectodermal aneurysm, Schwann cell tumor (schwannoma), meningiomas, atypical meningioma (meatypical meningioma), anaplastic meningioma; and pituitary adenoma. 在另一实施方案中,脑癌是胶质瘤、多形性胶质母细胞瘤、副神经节瘤或幕上原始神经外胚层肿瘤(suprantentorial primordial neuroectodermal tumor,sPNET)〇 In another embodiment, the brain cancer is a glioma, a glioblastoma multiforme tumor, paraganglioma, primitive neuroectodermal tumors or curtain (suprantentorial primordial neuroectodermal tumor, sPNET) square

[0316] 在另一实施方案中,可能与突变IDH酶活性有关的癌症是白血病,例如急性骨髓性白血病(acute myeloid leukemia,AML)、骨髓增生异常综合征(myelodysplastic syndrome,MDS)、慢性髓细胞性白血病(chronic myelogenous leukemia,CML)、骨髓增生性肿瘤(myeloproliferative neoplasm,MPN)、MPN转化的AML、MDS转化的AML、del (5q)相关性高风险MDS或AML、急变期慢性髓细胞性白血病、血管免疫母细胞性淋巴瘤和急性淋巴母细胞性白血病。 [0316] In another embodiment, mutations may IDH activity related cancer is a leukemia such as acute myeloid leukemia (acute myeloid leukemia, AML), myelodysplastic syndrome (myelodysplastic syndrome, MDS), chronic myelocytic leukemia (chronic myelogenous leukemia, CML), myeloproliferative neoplasms (myeloproliferative neoplasm, MPN), MPN transformed AML, MDS transformed AML, del (5q) associated with the high risk MDS or AML, cell blastic phase chronic myelogenous leukemia , angioimmunoblastic lymphoma, and acute lymphoblastic leukemia.

[0317] 在一个实施方案中,可能与突变IDH酶活性有关的癌症是皮肤癌,包括黑色素瘤。 [0317] In one embodiment, the mutant IDH activity may be related to cancer is skin cancer, including melanoma. 在另一实施方案中,可能与突变IDH酶活性有关的癌症是前列腺癌、乳腺癌、甲状腺癌、结肠癌或肺癌。 In another embodiment, the mutation may be cancer IDH activity is prostate cancer, breast cancer, thyroid cancer, colon cancer or lung cancer. 在另一实施方案中,可能与突变IDH酶活性有关的癌症是肉瘤,包括中心性软骨肉瘤、中心性和骨膜软骨瘤和纤维肉瘤。 In another embodiment, the mutation may be IDH activity is cancer sarcomas, including chondrosarcoma central, central and periosteal chondroma and fibrosarcoma. 在另一实施方案中,可能与突变IDH酶活性有关的癌症是胆管细胞型肝癌。 In another embodiment, the mutation may IDH activity is related cancers cholangiocarcinoma.

[0318] 在某些实施方案中,本文所述的化合物可以用于治疗增生性疾病,例如癌瘤,包括(但不限于)Kit介导的癌瘤、腺癌、鳞状细胞癌、腺鳞癌、畸胎癌、头颈部癌、脑癌、颅内癌瘤、 胶质母细胞瘤(包括PDGFR介导的胶质母细胞瘤)、多形性胶质母细胞瘤(包括PDGFR介导的多形性胶质母细胞瘤)、神经母细胞瘤、喉癌、2A和2B型多发性内分泌腺瘤(MENS 2A和MENS 2B)(包括RET介导的MENS)、甲状腺癌(包括散发性甲状腺髓样癌和家族性甲状腺髓样癌)、 甲状腺乳头状癌、甲状旁腺癌(包括任何RET介导的甲状腺癌)、滤泡状甲状腺癌、间变性甲状腺癌、支气管类癌、燕麦细胞癌、肺癌、小细胞肺癌(包括FLT3和/或Kit介导的小细胞肺癌)、非小细胞肺癌、胃/胃癌、胃肠癌、胃肠道间质瘤(gastrointestinal stromal tumor, GIST)(包括Kit介导的GIST和PDGFR α介导的GIST)、结肠癌、结肠直肠 [0318] In certain embodiments, the compounds described herein may be used for the treatment of proliferative diseases such as cancer, including (but not limited to) Kit-mediated carcinomas, adenocarcinoma, squamous cell carcinoma, adenosquamous carcinoma, teratocarcinoma, head and neck cancer, brain cancer, intracranial carcinoma, glioblastoma (glioblastoma including PDGFR-mediated), glioblastoma multiforme tumors (including PDGFR-mediated pleomorphic glioblastoma), neuroblastoma, larynx, 2A, and multiple endocrine neoplasia type 2B (MENS 2A and MENS 2B) (including mediated MENS RET), thyroid cancer (including sporadic medullary thyroid carcinoma and familial medullary thyroid cancer), papillary thyroid carcinoma, parathyroid carcinoma (including any RET-mediated thyroid carcinoma), follicular thyroid carcinoma, anaplastic thyroid cancer, bronchial carcinoid, oat cell cancer, lung cancer, small cell lung cancer (including FLT3 and / or Kit-mediated small cell lung cancer), non-small cell lung cancer, stomach / gastric cancer, gastrointestinal cancer, gastrointestinal stromal tumors (gastrointestinal stromal tumor, GIST) (including Kit-mediated GIST and PDGFR α mediated GIST), colon carcinoma, colorectal 癌、胰腺癌、胰岛细胞癌、肝/肝癌、肝转移、膀胱癌、肾细胞癌(包括TOGFR介导的肾细胞癌)、泌尿生殖道癌、卵巢癌(包括Kit介导和/或TOGFR介导的卵巢癌)、子宫内膜癌(包括CSF-IR介导的子宫内膜癌)、 子宫颈癌、乳腺癌(包括FLT3介导和/或PDGFR介导的乳腺癌)、前列腺癌(包括Kit介导的前列腺癌)、生殖细胞肿瘤(包括Kit介导的生殖细胞肿瘤)、精原细胞瘤(包括Kit介导的精原细胞瘤)、无性细胞瘤(包括Kit介导的无性细胞瘤)、黑色素瘤(包括PDGFR介导的黑色素瘤)、骨转移(包括CSF-IR介导的骨转移)、转移性瘤(包括VEGFR介导的肿瘤)、间质肿瘤、神经内分泌肿瘤、肿瘤血管生成(包括VEGFR介导的肿瘤血管生成)和混合性中胚叶肿瘤。 Cancer, pancreatic cancer, islet cell carcinoma, hepatic / liver cancer, liver cancer, bladder cancer, renal cell cancer (including renal cell carcinoma TOGFR mediated), genitourinary tract, ovarian cancer (including Kit-mediated and / or dielectric TOGFR mediated ovarian cancer), endometrial cancer (including endometrial CSF-IR mediated cancer), cervical cancer, breast cancer (including breast FLT3-mediated and / or PDGFR-mediated), prostate cancer (including Kit-mediated prostate cancer), germ cell tumors (including germ cell tumors Kit mediated), seminoma (including seminoma Kit mediated), dysgerminoma (including Kit-mediated dysgerminomas ), melanoma (including PDGFR-mediated melanoma), bone metastases (including bone metastases CSF-IR mediated), metastatic tumors (including VEGFR-mediated tumor), stromal tumors, neuroendocrine tumors, tumor angiogenesis and generating mixed mesodermal tumors (tumor angiogenesis including VEGFR-mediated generation).

[0319]在某些实施方案中,增生性疾病是肉瘤,包括(但不限于)PDGFR介导的肉瘤、骨肉瘤、骨原性肉瘤、骨癌、胶质瘤(包括PDGFR介导和/或CSF-IR介导的胶质瘤)、星形细胞瘤、动脉瘤(包括VEGFR介导的动脉瘤)、卡波西肉瘤、癌肉瘤、血管肉瘤(包括VEGFR3介导的血管肉瘤)和淋巴管肉瘤(包括VEGFR3介导的淋巴管肉瘤)。 [0319] In certain embodiments, the proliferative disorder is sarcoma, including (but not limited to) PDGFR-mediated sarcomas, osteosarcoma, osteogenic sarcoma, bone cancer, glioma (including PDGFR-mediated and / or CSF-IR mediated glioma), astrocytoma, aneurysm (including VEGFR-mediated aneurysm), Kaposi's sarcoma, carcinoma, angiosarcoma (including VEGFR3-mediated hemangiosarcoma) and lymphatic sarcomas (including VEGFR3-mediated lymphangiosarcoma).

[0320] 在某些实施方案中,增生性疾病是恶性血液病。 [0320] In certain embodiments, the proliferative disease is a hematologic malignancy. 在某些实施方案中,增生性疾病是复发性恶性血液病。 In certain embodiments, the proliferative disease is relapsed hematologic malignancies. 在某些实施方案中,增生性疾病是难治性恶性血液病。 In certain embodiments, the proliferative disease is refractory hematologic malignancies. 在某些实施方案中,增生性疾病是耐药性恶性血液病。 In certain embodiments, the proliferative disease is drug-resistant hematologic malignancies. 在某些实施方案中,增生性疾病是多重耐药性恶性血液病。 In certain embodiments, the proliferative disease is a multi-drug resistant hematologic malignancies. 在某些实施方案中,增生性疾病是耐Bcr-Abl激酶抑制剂性恶性血液病。 In certain embodiments, the proliferative disorder is resistant Bcr-Abl kinase inhibitors hematologic malignancies. 在某些实施方案中,增生性疾病是耐伊马替尼(imatinib)性恶性血液病。 In certain embodiments, the proliferative disorder is resistant to imatinib (Imatinib) hematologic malignancies. 在某些实施方案中,增生性疾病是耐达沙替尼(dasatinib)性恶性血液病。 In certain embodiments, the proliferative disorder is resistant to dasatinib (dasatinib) hematologic malignancies. 在某些实施方案中,增生性疾病是耐尼洛替尼(nilatinib)性恶性血液病。 In certain embodiments, the proliferative disorder is nilatinib (nilatinib) hematologic malignancies. 在某些实施方案中,增生性疾病是耐博舒替尼(bosutinib)性恶性血液病。 In certain embodiments, the proliferative disorder is resistant bosutinib (Bosutinib) hematologic malignancies. 在某些实施方案中,增生性疾病是耐阿糖胞苷(cytarabine)性恶性血液病。 In certain embodiments, the proliferative disorder is resistant to cytarabine (cytarabine) hematologic malignancies.

[0321] 在某些实施方案中,恶性血液病是骨髓瘤、白血病、骨髓增生性疾病、急性骨髓性白血病(AML)(包括FLT3介导和/或KIT介导和/或CSFlR介导的急性骨髓性白血病)、慢性骨髓性白血病(CML)(包括FLT3介导和/或PDGFR介导的慢性骨髓性白血病)、骨髓增生异常白血病(包括FLT3介导的骨髓增生异常白血病)、骨髓增生异常综合征(包括FLT3介导和/或Kit介导的骨髓增生异常综合征)、特发性嗜酸性粒细胞增多综合征(idiopathic hypereosinophilic syndrome,HES)(包括PDGFR介导的HES)、慢性嗜酸性粒细胞白血病(chronic eosinophilic leukemia,CEL)(包括F1DGFR介导的CEL)、慢性单核细胞性白血病(chronic myelomonocytic leukemia,CMML)、肥大细胞白血病(包括Kit介导的肥大细胞白血病)或系统性肥大细胞增多症(包括Kit介导的系统性肥大细胞增多症)。 [0321] In certain embodiments, the hematological malignancy is a myeloma, myeloproliferative disorders, acute FLT3-mediated and / or KIT-mediated and / or CSFlR mediated leukemia acute myelogenous leukemia (of AML) (including myeloid leukemia), chronic myelogenous leukemia (CML) (including chronic myelogenous leukemia, FLT3-mediated and / or PDGFR-mediated), myelodysplastic leukemia (including FLT3-mediated myelodysplastic leukemia), myelodysplastic sign (including bone marrow FLT3-mediated and / or Kit-mediated myelodysplastic syndrome), idiopathic eosinophilic hypereosinophilic syndrome (idiopathic hypereosinophilic syndrome, HES) (including PDGFR-mediated HES), chronic eosinophilic leukemia (chronic eosinophilic leukemia, CEL) (including CEL F1DGFR mediated), chronic monocytic leukemia (chronic myelomonocytic leukemia, CMML), mast cell leukemia (including Kit-mediated mast cell leukemia), or systemic mast cell vera (including Kit-mediated systemic mastocytosis).

[0322] 在某些实施方案中,恶性血液病是淋巴瘤、淋巴组织增生性疾病、急性淋巴母细胞性白血病(acute lymphoblastic leukemia,ALL)、B细胞急性淋巴母细胞性白血病、T细胞急性淋巴母细胞性白血病、慢性淋巴细胞性白血病(chronic lymphocytic leukemia, CLL)、自然杀伤(natural killer,NK)细胞白血病、B细胞淋巴瘤、T细胞淋巴瘤或自然杀伤(NK)细胞淋巴瘤。 [0322] In certain embodiments, the hematological malignancy is a lymphoma, lymphoproliferative diseases, acute lymphoblastic leukemia (acute lymphoblastic leukemia, ALL), B cell acute lymphoblastic leukemia, T-cell acute lymphoblastic leukemia, chronic lymphocytic leukemia (chronic lymphocytic leukemia, CLL), natural killer (natural killer, NK) cell leukemia, B-cell lymphoma, T-cell lymphoma, or natural killer (NK) cell lymphoma.

[0323] 在一个实施方案中,恶性血液病是骨髓增生异常综合征(MDS)。 [0323] In one embodiment, the hematological malignancy is a myelodysplastic syndrome (MDS).

[0324] 在某些实施方案中,恶性血液病是朗格罕细胞组织细胞增生症(包括CSF-IR介导和/或FLT3介导的朗格罕细胞组织细胞增生症)、肥大细胞肿瘤或肥大细胞增多症。 [0324] In certain embodiments, the hematological malignancy is a Langerhans cell histiocytosis (including CSF-IR mediated and / or FLT3-mediated Langerhans cell histiocytosis), or mast cell tumors mastocytosis.

[0325] 在某些实施方案中,恶性血液病是白血病。 [0325] In certain embodiments, the hematological malignancy is a leukemia. 在某些实施方案中,恶性血液病是复发性白血病。 In certain embodiments, the hematological malignancy is relapsed leukemia. 在某些实施方案中,恶性血液病是难治性白血病。 In certain embodiments, the hematological malignancy is refractory leukemia. 在某些实施方案中,恶性血液病是耐药性白血病。 In certain embodiments, the hematological malignancy is a drug-resistant leukemia. 在某些实施方案中,恶性血液病是多重耐药性白血病。 In certain embodiments, the hematological malignancy is multiple drug-resistant leukemia. 在某些实施方案中,恶性血液病是耐Bcr-Abl激酶抑制剂性白血病。 In certain embodiments, the hematological malignancy is a Bcr-Abl kinase inhibitor-resistant leukemia. 在某些实施方案中,恶性血液病是耐伊马替尼性白血病。 In certain embodiments, the hematological malignancy is a leukemia resistant to imatinib. 在某些实施方案中,恶性血液病是耐达沙替尼性白血病。 In certain embodiments, the hematological malignancy is a leukemia resistant to dasatinib. 在某些实施方案中,恶性血液病是耐尼洛替尼性白血病。 In certain embodiments, the hematological malignancy is a leukemia nilatinib. 在某些实施方案中,恶性血液病是耐博舒替尼性白血病。 In certain embodiments, the hematological malignancy is a leukemia resistant bosutinib.

[0326] 在某些实施方案中,恶性血液病是耐阿糖胞苷性白血病。 [0326] In certain embodiments, the hematological malignancy is a leukemia resistant to cytarabine.

[0327] 在某些实施方案中,白血病是急性白血病。 [0327] In certain embodiments, the leukemia is acute leukemia. 在某些实施方案中,白血病是复发性急性白血病。 In certain embodiments, the leukemia is relapsed acute leukemia. 在某些实施方案中,白血病是难治性急性白血病。 In certain embodiments, the leukemia is refractory acute leukemia. 在某些实施方案中,白血病是耐药性急性白血病。 In certain embodiments, the leukemia is acute leukemia drug. 在某些实施方案中,白血病是多重耐药性急性白血病。 In certain embodiments, the leukemia is acute leukemia multidrug resistance. 在某些实施方案中,白血病是耐Bcr-Abl激酶抑制剂性急性白血病。 In certain embodiments, the leukemia is resistant Bcr-Abl kinase inhibitors of acute leukemia. 在某些实施方案中,白血病是耐伊马替尼性急性白血病。 In certain embodiments, an imatinib-resistant leukemia is acute leukemia. 在某些实施方案中,白血病是耐达沙替尼性急性白血病。 In certain embodiments, dasatinib-resistant leukemia is acute leukemia. 在某些实施方案中,白血病是耐尼洛替尼性急性白血病。 In certain embodiments, the leukemia is nilatinib acute leukemia. 在某些实施方案中,白血病是耐博舒替尼性急性白血病。 In certain embodiments, the leukemia is resistant bosutinib acute leukemia. 在某些实施方案中,白血病是耐阿糖胞苷性急性白血病。 In certain embodiments, the leukemia is acute leukemia resistant to cytarabine. 在某些实施方案中,白血病是遗传性白血病。 In certain embodiments, the leukemia is hereditary leukemia. 在某些实施方案中,遗传性白血病是重型先天性中性粒细胞减少症(severe congenital neutropenia,SCN)。 In certain embodiments, the leukemia is severe hereditary congenital neutropenia neutropenia (severe congenital neutropenia, SCN). 在某些实施方案中,遗传性白血病是伴有急性髓细胞性白血病的家族性血小板病症(familial platelet disorder with acute myelogenous leukemia,FDP/AML)。 In certain embodiments, hereditary leukemia is acute myelogenous leukemia with familial platelet disorder (familial platelet disorder with acute myelogenous leukemia, FDP / AML). 在某些实施方案中,白血病是由LEFl引起。 In certain embodiments, the leukemia is caused by LEFl. 在某些实施方案中,白血病是由LEFl介导。 In certain embodiments, the leukemia is mediated by the LEFl. 在某些实施方案中,白血病是由GSK3引起。 In certain embodiments, the leukemia is caused by a GSK3.

[0328] 在某些实施方案中,白血病是ALL。 [0328] In certain embodiments, the leukemia is ALL. 在某些实施方案中,白血病是复发性ALL。 In certain embodiments, the leukemia is relapsed ALL. 在某些实施方案中,白血病是难治性ALL。 In certain embodiments, the leukemia is refractory ALL. 在某些实施方案中,白血病是耐药性ALL。 In certain embodiments, the leukemia is resistant ALL. 在某些实施方案中,白血病是多重耐药性ALL。 In certain embodiments, the leukemia is multi-drug resistant ALL. 在某些实施方案中,白血病是耐Bcr-Abl激酶抑制剂性ALL。 In certain embodiments, the leukemia is resistant Bcr-Abl kinase inhibitors of ALL. 在某些实施方案中,白血病是耐伊马替尼性ALL。 In certain embodiments, the leukemia is resistant to imatinib resistance ALL. 在某些实施方案中,白血病是耐达沙替尼性ALL。 In certain embodiments, the leukemia is resistant to dasatinib of ALL. 在某些实施方案中,白血病是耐尼洛替尼性ALL。 In certain embodiments, the leukemia is nilatinib of ALL. 在某些实施方案中,白血病是耐博舒替尼性ALL。 In certain embodiments, the leukemia is resistant bosutinib of ALL. 在某些实施方案中,白血病是耐阿糖胞苷性ALL。 In certain embodiments, the leukemia is resistant to cytarabine resistance ALL.

[0329] 在一个实施方案中,ALL是起源于骨髓(B细胞)、胸腺(T细胞)或淋巴结的胚细胞的白血病。 [0329] In one embodiment, ALL is derived from bone marrow (B cells), thymus (T-cells), or lymph nodes of leukemia blasts. 根据法美英(French-American-British,FAB)形态学分类,将ALL分类为Ll-看似成熟的淋巴母细胞(T细胞或前B细胞)、L2-不成熟和多形性(多种形状)淋巴母细胞(T细胞或前B细胞)和L3-淋巴母细胞(B细胞;伯基特细胞(BurkittS cell))。 Method according to US and UK (French-American-British, FAB) morphological classification, the classification of ALL appears to Ll- mature lymphoblasts (T-cells or pre-B cells), the immature and the L2-pleomorphic (a variety of shapes ) lymphoblasts (T-cells or pre-B cells), and lymphoblasts L3- (B-cells; Burkitt's cells (BurkittS cell)). 在另一实施方案中, ALL起源于骨髓胚细胞(B细胞)。 In another embodiment, ALL blast cells derived from bone marrow (B cells). 在又一实施方案中,ALL起源于胸腺(T细胞)。 In yet another embodiment, ALL originated in the thymus (T cells). 在又一实施方案中,ALL起源于淋巴结。 In yet another embodiment, ALL originated in the lymph nodes. 在又一实施方案中,ALL是特征为看似成熟的淋巴母细胞(T细胞或前B细胞)的Ll型。 In yet another embodiment, ALL is characterized by a seemingly mature lymphoblasts (T-cells or pre-B cells) type Ll. 在又一实施方案中,ALL是特征为不成熟和多形(多种形状)淋巴母细胞(T 细胞或前B细胞)的L2型。 In yet another embodiment, ALL is characterized by immature polymorphonuclear (a variety of shapes) lymphoblasts (T-cells or pre-B cells) type L2. 在又一实施方案中,ALL是特征为淋巴母细胞(B细胞;伯基特细胞) 的L3型。 In yet another embodiment, ALL is characterized by lymphoblastoid cells (B cells; Burkitt's cells) L3 type.

[0330] 在某些实施方案中,白血病是AML。 [0330] In certain embodiments, the leukemia is AML. 在某些实施方案中,白血病是复发性AML。 In certain embodiments, the leukemia is relapsed AML. 在某些实施方案中,白血病是难治性AML。 In certain embodiments, the leukemia is refractory AML. 在某些实施方案中,白血病是耐药性AML。 In certain embodiments, drug-resistant leukemia is AML. 在某些实施方案中,白血病是多重耐药性AML。 In certain embodiments, multi-drug resistant leukemia is AML. 在某些实施方案中,白血病是耐Bcr-Abl激酶抑制剂性AML。 In certain embodiments, the leukemia is resistant Bcr-Abl kinase inhibitors of AML. 在某些实施方案中,白血病是耐伊马替尼性AML。 In certain embodiments, the leukemia is resistant to imatinib of AML. 在某些实施方案中,白血病是耐达沙替尼性AML。 In certain embodiments, the leukemia is resistant to dasatinib of AML. 在某些实施方案中,白血病是耐尼洛替尼性AML。 In certain embodiments, the leukemia is nilatinib of AML. 在某些实施方案中,白血病是耐博舒替尼性AML。 In certain embodiments, the leukemia is resistant bosutinib of AML. 在某些实施方案中,白血病是耐阿糖胞苷性AML。 In certain embodiments, the leukemia is resistant to cytarabine resistance AML. 在某些实施方案中,AML 具有RAS突变。 In certain embodiments, AML with RAS mutation. 在某些实施方案中,RAS突变是NRAS、KRAS或HRAS。 In certain embodiments, RAS mutation is NRAS, KRAS, or HRAS. 在某些实施方案中,RAS突变是NRAS。 In certain embodiments, RAS mutation is NRAS. 在某些实施方案中,RAS突变是KRAS。 In certain embodiments, RAS is mutated KRAS. 在某些实施方案中,RAS突变是HRAS。 In certain embodiments, RAS mutations HRAS.

[0331] 在某些实施方案中,AML是未分化AML (MO)、成髓细胞白血病(Ml)、成髓细胞白血病(M2)、早幼粒细胞性白血病(M3或M3变异体[M3V])、单核细胞性白血病(M4或伴有嗜酸性粒细胞增多的M4变异体[M4E])、单核细胞性白血病(M5)、红白血病(M6)或巨核细胞白血病(M7)。 [0331] In certain embodiments, AML is undifferentiated AML (MO), myeloblasts leukemia (Ml), myeloblastic leukemia (M2), promyelocytic leukemia (M3 or M3 variant [M3V] ), monocytic leukemia (M4 or with the increase of eosinophils M4 variant [M4E]), monocytic leukemia (M5), erythroleukemia (M6) or megakaryoblastic leukemia (M7). 在一个实施方案中,AML是未分化AML (MO)。 In one embodiment, AML is undifferentiated AML (MO). 在另一实施方案中,AML是成髓细胞白血病(Ml)。 In another embodiment, AML is myeloblastic leukemia (Ml). 在又一实施方案中,AML是成髓细胞白血病(M2)。 In yet another embodiment, AML is myeloblastic leukemia (M2). 在又一实施方案中,AML是早幼粒细胞性白血病(M3或M3变异体[M3V])。 In yet another embodiment, AML is promyelocytic leukemia (M3 or M3 variant [M3V]). 在又一实施方案中,AML是单核细胞性白血病(M4或伴有嗜酸性粒细胞增多的M4变异体[M4E])。 In yet another embodiment, AML is monocytic leukemia (M4 or with the increase of eosinophils M4 variant [M4E]). 在又一实施方案中,AML是单核细胞性白血病(M5)。 In yet another embodiment, AML is monocytic leukemia (M5). 在又一实施方案中,AML是红白血病(M6)。 In yet another embodiment, AML is erythroleukemia (M6). 在又一实施方案中,AML是巨核细胞白血病(M7)。 In yet another embodiment, AML is megakaryoblastic leukemia (M7). 在某些实施方案中,白血病是慢性白血病。 In certain embodiments, the leukemia is chronic leukemia. 在某些实施方案中,白血病是复发性慢性白血病。 In certain embodiments, the leukemia is relapsed chronic leukemia. 在某些实施方案中,白血病是难治性慢性白血病。 In certain embodiments, the leukemia is refractory chronic leukemia. 在某些实施方案中,白血病是耐药性慢性白血病。 In certain embodiments, the leukemia is resistant chronic leukemia. 在某些实施方案中,白血病是多重耐药性慢性白血病。 In certain embodiments, the leukemia is chronic leukemia multidrug resistance. 在某些实施方案中,白血病是耐Bcr-Abl激酶抑制剂性慢性白血病。 In certain embodiments, the leukemia is resistant Bcr-Abl kinase inhibitors chronic leukemia. 在某些实施方案中,白血病是耐伊马替尼性慢性白血病。 In certain embodiments, the leukemia is chronic imatinib-resistant leukemia. 在某些实施方案中,白血病是耐达沙替尼性慢性白血病。 In certain embodiments, the leukemia is dasatinib-resistant chronic leukemia. 在某些实施方案中,白血病是耐尼洛替尼性慢性白血病。 In certain embodiments, the leukemia is chronic nilatinib leukemia. 在某些实施方案中,白血病是耐博舒替尼性慢性白血病。 In certain embodiments, the leukemia is resistant bosutinib chronic leukemia. 在某些实施方案中,白血病是耐阿糖胞苷性慢性白血病。 In certain embodiments, the leukemia is chronic leukemia resistant to cytarabine.

[0332] 在某些实施方案中,白血病是CLL。 [0332] In certain embodiments, the leukemia is CLL. 在某些实施方案中,白血病是复发性CLL。 In certain embodiments, the leukemia is relapsed CLL. 在某些实施方案中,白血病是难治性CLL。 In certain embodiments, the leukemia is refractory CLL. 在某些实施方案中,白血病是耐药性CLL。 In certain embodiments, the leukemia is resistant CLL. 在某些实施方案中,白血病是多重耐药性CLL。 In certain embodiments, the leukemia is multidrug resistance CLL. 在某些实施方案中,白血病是耐Bcr-Abl激酶抑制剂性CLL。 In certain embodiments, the leukemia is resistant Bcr-Abl kinase inhibitors of CLL. 在某些实施方案中,白血病是耐伊马替尼性CLL。 In certain embodiments, the leukemia is resistant to imatinib of CLL. 在某些实施方案中,白血病是耐达沙替尼性CLL。 In certain embodiments, the leukemia is resistant to dasatinib of CLL. 在某些实施方案中,白血病是耐尼洛替尼性CLL。 In certain embodiments, the leukemia is nilatinib of CLL. 在某些实施方案中,白血病是耐博舒替尼性CLL。 In certain embodiments, the leukemia is resistant bosutinib of CLL. 在某些实施方案中,白血病是耐阿糖胞苷性CLL。 In certain embodiments, the leukemia is resistant to cytarabine resistance CLL.

[0333] 在某些实施方案中,白血病是CML。 [0333] In certain embodiments, the leukemia is CML. 在某些实施方案中,白血病是复发性CML。 In certain embodiments, the leukemia is relapsed CML. 在某些实施方案中,白血病是难治性CML。 In certain embodiments, the leukemia is refractory CML. 在某些实施方案中,白血病是耐药性CML。 In certain embodiments, the leukemia is resistant CML. 在某些实施方案中,白血病是多重耐药性CML。 In certain embodiments, the leukemia is multidrug resistant CML. 在某些实施方案中,白血病是耐Bcr-Abl激酶抑制剂性CML。 In certain embodiments, the leukemia is resistant Bcr-Abl kinase inhibitors of CML. 在某些实施方案中,白血病是耐伊马替尼性CML。 In certain embodiments, the leukemia is resistant to imatinib of CML. 在某些实施方案中,白血病是耐达沙替尼性CML。 In certain embodiments, the leukemia is resistant to dasatinib of CML. 在某些实施方案中,白血病是耐尼洛替尼性CML。 In certain embodiments, the leukemia is nilatinib of CML. 在某些实施方案中,白血病是耐博舒替尼性CML。 In certain embodiments, the leukemia is resistant bosutinib of CML. 在某些实施方案中,白血病是耐阿糖胞苷性CML。 In certain embodiments, the leukemia is resistant to cytarabine resistance CML. 在某些实施方案中,白血病是青少年CML。 In certain embodiments, the leukemia is juvenile CML. 在某些实施方案中,白血病是具有一个或多个NF-I突变的青少年CML。 In certain embodiments, the leukemia is having one or more mutations in NF-I juvenile CML.

[0334] 在某些实施方案中,白血病是T细胞白血病。 [0334] In certain embodiments, the leukemia is T cell leukemia. 在一个实施方案中,T细胞白血病是外周T细胞白血病、T细胞淋巴母细胞性白血病、皮肤T细胞白血病和成人T细胞白血病。 In one embodiment, T-cell leukemia is a peripheral T-cell leukemia, T-cell lymphoblastic leukemia, cutaneous T-cell leukemia, and adult T-cell leukemia. 在另一实施方案中,T细胞白血病是外周T细胞白血病。 In another embodiment, T-cell leukemia is a peripheral T-cell leukemia. 在又一实施方案中,T细胞白血病是T细胞淋巴母细胞性白血病。 In yet another embodiment, T-cell leukemia is T-cell lymphoblastic leukemia. 在又一实施方案中,T细胞白血病是皮肤T细胞白血病。 In yet another embodiment, T-cell leukemia is cutaneous T-cell leukemia. 在又一实施方案中,T细胞白血病是成人T细胞白血病。 In yet another embodiment, T-cell leukemia is adult T cell leukemia.

[0335] 在某些实施方案中,白血病是费城阳性的。 [0335] In certain embodiments, the leukemia is Philadelphia positive. 在一个实施方案中,费城阳性白血病是费城阳性AML,包括(但不限于)未分化AML (MO)、成髓细胞白血病(Ml)、成髓细胞白血病(M2)、早幼粒细胞性白血病(M3或M3变异体[M3V])、单核细胞性白血病(M4或伴有嗜酸性粒细胞增多的M4变异体[M4E])、单核细胞性白血病(M5)、红白血病(M6)或巨核细胞白血病(M7)。 In one embodiment, Philadelphia positive leukemia is Philadelphia positive of AML, including (but not limited to) undifferentiated AML (MO), myeloblasts leukemia (of Ml), myeloblastic leukemia (M2), promyelocytic leukemia ( M3 or M3 variant [M3V]), monocytic leukemia (increased M4 or with eosinophils M4 variant [M4E]), monocytic leukemia (M5), erythroleukemia (M6) or megakaryocytes leukemia (M7). 在另一实施方案中,费城阳性白血病是费城阳性ALL。 In another embodiment, Philadelphia positive leukemia is Philadelphia positive ALL.

[0336] 在某些实施方案中,增生性疾病是癌症,包括(但不限于)头颈部癌症(起源于唇、 口腔、口咽、舌、喉、鼻咽、鼻腔、鼻旁窦或唾液腺)、肺癌(包括小细胞肺癌和非小细胞肺癌)、 胃肠道癌(包括食道癌)、胃癌、结肠直肠癌、肛门癌、胰腺癌、肝癌、胆囊癌、肝外胆管癌、乏特壶腹癌、乳腺癌、妇科癌症(包括子宫颈癌)、子宫体癌、阴道癌、外阴癌、卵巢癌、妊娠滋养细胞肿瘤、睾丸癌、尿路癌(包括肾癌)、膀胱癌、前列腺癌、阴茎癌、尿道癌、神经系统肿瘤、 内分泌肿瘤(包括类癌瘤和胰岛细胞瘤)、嗜铬细胞瘤、肾上腺皮质癌、甲状旁腺腺癌和转移至内分泌腺。 [0336] In certain embodiments, the proliferative disease is cancer, including (but not limited to) the head and neck cancer (originated in the lip, oral cavity, oropharynx, tongue, larynx, nasopharynx, nasal cavity, paranasal sinuses or salivary gland ), lung (including small cell lung cancer and non-small cell lung carcinoma), gastrointestinal cancers (including esophageal cancer), gastric cancer, colorectal cancer, anal cancer, pancreatic cancer, liver cancer, gallbladder cancer, extrahepatic bile duct cancer, pot Vater abdominal cancer, breast cancer, gynecological (including cervical cancer), endometrial cancer, vaginal cancer, vulvar cancer, ovarian cancer, gestational trophoblastic tumors, testicular cancers, urinary tract cancers (including renal), bladder cancer, prostate cancer , penile cancer, urethral cancer, nervous system tumors, endocrine tumors (including carcinoid and islet cell tumors), pheochromocytoma, adrenal cortical carcinoma, parathyroid carcinoma and metastases to endocrine glands.

[0337] 癌症的其它实例是基底细胞癌、鳞状细胞癌、软骨肉瘤(在软骨细胞中出现的癌症)、间胚叶性软骨肉瘤、软组织肉瘤(包括可能在任何中胚层组织(肌肉、腱、传送血液或淋巴的血管、关节和脂肪)中出现的恶性肿瘤)、软组织肉瘤(包括腺泡状软组织肉瘤)、血管肉瘤、纤维肉瘤、平滑肌肉瘤、脂肪肉瘤、恶性纤维组织细胞瘤、血管外皮细胞瘤、间叶瘤、许旺细胞瘤、外周性神经外胚叶肿瘤、横纹肌肉瘤、滑膜肉瘤、妊娠滋养细胞肿瘤(其中在妊娠后在子宫中形成的组织变成癌性的恶性病)、霍奇金淋巴瘤和喉癌。 [0337] Other examples of cancers are basal cell carcinoma, squamous cell carcinoma, chondrosarcoma (a cancer occurring in chondrocytes), between embryonic mesenchymal chondrosarcoma, soft tissue sarcomas (including possible in any of the mesodermal tissues (muscles, tendons , malignant transfer blood or lymph vessels, joints and fat) occurring), soft tissue sarcomas (including alveolar soft part sarcoma), angiosarcoma, fibrosarcoma, leiomyosarcoma, liposarcoma, malignant fibrous histiocytoma, hemangiopericytoma cell tumors, mesenchymal tumors, schwannomas, peripheral neuroectodermal tumors, rhabdomyosarcoma, synovial sarcoma, gestational trophoblastic tumor (which becomes tissue formed after gestation in the uterus cancerous malignancies) , Hodgkin's lymphoma and laryngeal cancer.

[0338] 在某些实施方案中,增生性疾病是一种非恶性的增生性疾病,包括(但不限于)动脉粥样硬化(包括PDGFR介导的动脉粥样硬化)、血管成形术后再狭窄(PDGFR介导的再狭窄) 和纤维增生性疾病(包括闭塞性细支气管炎和特发性骨髓纤维化)。 [0338] In certain embodiments, the proliferative disease is a non-malignant proliferative diseases, including (but not limited to) atherosclerosis (including PDGFR-mediated atherosclerosis), and then after angioplasty stenosis (PDGFR-mediated restenosis) and fibroproliferative disorders (including bronchiolitis obliterans and idiopathic myelofibrosis).

[0339] 在某些实施方案中,增生性疾病是一种与免疫功能紊乱、免疫缺陷或免疫调节有关的发炎性疾病或病症,包括(但不限于)自身免疫性疾病、组织移植排斥反应、移植物抗宿主疾病、伤口愈合、肾病、多发性硬化、甲状腺炎、1型糖尿病、结节病、过敏性鼻炎、发炎性肠病(包括克罗恩氏病(Crohn's disease)和溃疡性结肠炎(ulcerative colitis,UC))、系统性红斑狼疮(systemic lupus erythematosis,SLE)、关节炎、骨关节炎、类风湿性关节炎、 骨质疏松症、哮喘和慢性阻塞性肺病(chronic obstructive pulmonary disease,C0PD)。 [0339] In certain embodiments, the proliferative disease is an immune disorder, immunodeficiency or inflammatory immunomodulatory diseases or disorders associated, including (but not limited to) autoimmune diseases, tissue transplant rejection, graft versus host disease, wound healing, kidney disease, multiple sclerosis, thyroiditis, type 1 diabetes, sarcoidosis, allergic rhinitis, inflammatory bowel disease (including Crohn's disease (Crohn's disease) and ulcerative colitis (ulcerative colitis, UC)), systemic lupus erythematosus (systemic lupus erythematosis, SLE), arthritis, osteoarthritis, rheumatoid arthritis, osteoporosis, asthma and chronic obstructive pulmonary disease (chronic obstructive pulmonary disease, C0PD).

[0340] 在某些实施方案中,增生性疾病是一种传染性疾病。 [0340] In certain embodiments, the proliferative disease is an infectious disease. 在某些实施方案中,增生性疾病是真菌感染。 In certain embodiments, the proliferative disease is a fungal infection. 在某些实施方案中,传染性疾病是表面真菌病(例如花斑癣)。 In certain embodiments, the infectious disease is a fungal disease surface (e.g. tinea versicolor). 在某些实施方案中,传染性疾病是皮肤真菌病(例如表皮)。 In certain embodiments, the infectious disease is a fungal disease of the skin (e.g., epidermis). 在某些实施方案中,增生性疾病是皮下真菌病。 In certain embodiments, the proliferative disorder is subcutaneous mycoses. 在某些实施方案中,增生性疾病是全身真菌病。 In certain embodiments, the proliferative disease is systemic mycoses.

[0341] 在某些实施方案中,增生性疾病是白血病、成人T细胞白血病、早幼粒细胞性白血病、前B细胞白血病、淋巴瘤、套细胞淋巴瘤、乳腺癌、胰腺癌、前列腺癌、头颈部癌、卵巢癌、 黑色素瘤、神经胶质瘤、肝癌、肾癌、结肠直肠癌、横纹肌肉瘤、舌癌、胃癌、多发性骨髓瘤、膀胱癌、甲状腺癌、表皮样癌、肺癌、NSC肺癌或大细胞肺癌。 [0341] In certain embodiments, the proliferative disease is leukemia, adult T-cell leukemia, promyelocytic leukemia, pre-B cell leukemia, lymphoma, mantle cell lymphoma, breast cancer, pancreatic cancer, prostate cancer, head and neck cancer, ovarian cancer, melanoma, glioma, liver cancer, renal cancer, colorectal cancer, rhabdomyosarcoma, tongue carcinoma, gastric cancer, multiple myeloma, bladder cancer, thyroid cancer, epidermoid cancer, lung cancer, NSC lung cancer or large cell lung cancer.

[0342] 在某些实施方案中,增生性疾病是成人T细胞白血病、早幼粒细胞性白血病、前B细胞白血病、淋巴瘤、套细胞淋巴瘤、胰腺癌、前列腺癌、头颈部癌、卵巢癌、黑色素瘤、神经胶质瘤、肝癌、肾癌、结肠直肠癌、横纹肌肉瘤、舌癌、胃癌、多发性骨髓瘤、膀胱癌、甲状腺癌、 表皮样癌、NSC肺癌或大细胞肺癌。 [0342] In certain embodiments, the proliferative disorder is adult T cell leukemia, promyelocytic leukemia, pre-B cell leukemia, lymphoma, mantle cell lymphoma, pancreatic cancer, prostate cancer, head and neck cancer, ovarian cancer, melanoma, glioma, liver cancer, renal cancer, colorectal cancer, rhabdomyosarcoma, tongue carcinoma, gastric cancer, multiple myeloma, bladder cancer, thyroid cancer, epidermoid carcinoma, large cell lung cancer or the NSC lung cancer.

[0343] 在某些实施方案中,增生性疾病是白血病、成人T细胞白血病、早幼粒细胞性白血病、前B细胞白血病、淋巴瘤、套细胞淋巴瘤、乳腺癌、头颈部癌症、卵巢癌、结肠直肠癌、舌癌、多发性骨髓瘤或大细胞肺癌。 [0343] In certain embodiments, the proliferative disease is leukemia, adult T-cell leukemia, promyelocytic leukemia, pre-B cell leukemia, lymphoma, mantle cell lymphoma, breast cancer, head and neck cancer, ovarian cancer, colorectal cancer, tongue cancer, multiple myeloma, or large cell lung cancer.

[0344] 还提供了本文所述的化合物,其用于本文所述的治疗中。 [0344] Also provided compounds described herein, for the treatment described herein.

[0345] 还提供了本文所述的化合物的用途,其用于制造供本文所述的治疗用的药剂。 [0345] also provides the use of the compounds described herein, which is used for manufacturing a medicament for the treatment described herein. [0346]测定方法 [0346] Determination

[0347] 从一个不加干预和前瞻性的研究获得患者样品。 [0347] obtaining a sample from a patient without intervention and forward-looking research. 此研究包括来自18岁以上的经诊断患有急性骨髓性白血病(AML)的成人患者的样品。 This study included samples from adult patients 18 years and older diagnosed with acute myelogenous leukemia (AML) is.

[0348] 在一个实施方案中,数据采集方法如下进行:在第1天,收到骨髓(bone marrow, BM)或外周血(peripheral blood,PB)患者样品。 [0348] In one embodiment, the data collection method was performed as follows: On day 1, patients receive a sample of bone marrow (bone marrow, BM) or peripheral blood (peripheral blood, PB). 将一小部分与样品其余部分分离以供验证用,而大多数样品用培养基稀释并涂铺至96孔平板中,所述平板预先用所需化合物和化合物组合,例如本文所述的化合物或化合物组合准备。 A small portion of the sample separated from the rest for verification, and most samples were diluted with culture medium and plated into 96-well plates, and the plates in advance with a combination of the desired compound, or compounds described herein e.g. compound combination preparation. 每个孔中接种的活的白血病细胞的数目固定在8000个与32000个之间,取决于每个样品的白血病细胞的百分比。 The number of viable cells in each well leukemia seeded fixed between 8000 and 32,000, depending on the percentage of leukemic cells in each sample. 将这些平板孵育72小时并在第4天进行分析。 The plates were incubated for 72 hours and analyzed on day 4. 加入抗体以使用门控策略,基于FSC/SSC和不同表面标记物的表达或表达缺乏来鉴别白血病细胞。 Added to the antibody using gating strategy, based on the expression or expression of FSC / SSC and different surface markers to identify the lack of leukemic cells. 进行单克隆抗体选择以便使每个样品中白血病细胞的鉴别最佳化。 Monoclonal antibody selection in order to identify the best of leukemic cells in each sample.

[0349] 在一个实施方案中,组合中包括生物标记物的非限制性实例,例如生物标记物CD34、CD45、CDl 17和HLADR,这些被称为AML的“骨干标记物”(van Dongen,J · J ·和A · Orf ao, EuroFlow:Resetting leukemia and lymphoma immunophenotyping . Basis for companion diagnostics and personalized medicine,Leukemia,2012,26,1899-907) 〇 [0349] In one embodiment, non-limiting examples include combinations of biomarkers, e.g. biomarkers CD34, CD45, CDl 17, and HLADR, these are called AML the "backbone marker" (van Dongen, J and · J · A · Orf ao, EuroFlow:. Resetting leukemia and lymphoma immunophenotyping Basis for companion diagnostics and personalized medicine, leukemia, 2012,26,1899-907) billion

[0350] 在一个实施方案中,使用例如⑶117/⑶45、CD34/⑶45和HLADR/⑶45的抗体组合D 在缺乏膜联蛋白-V-FITC染色的情况下,活的白血病细胞通过其光散射性质(FSCint/hi/ SSCint)来鉴别。 In the case [0350] In one embodiment, for example, ⑶117 / ⑶45, CD34 / ⑶45 and HLADR / ⑶45 combination of antibodies in the absence of Annexin D -V-FITC staining live leukemia cells through its light scattering properties ( FSCint / hi / SSCint) to identify. 进行FSC/SSC选择以排除碎片。 Be FSC / SSC choose to exclude debris. 收到样品时细胞活力的平均百分比是80%, 并且只在活力超过50%时才加工样品。 The average percentage of cell viability was 80% when the sample is received, and only when more than 50% viability processed samples.

[0351] 在一个实施方案中,样品验证如下进行:在无菌条件下提取BM和PB样品并且在实验室中在提取24小时内收到样品。 [0351] In one embodiment, the sample verified as follows: BM and PB samples were extracted under sterile conditions and extracting received samples in 24 hours in the laboratory. 初次分析评估病态细胞的数目和其活力。 Initial analysis and evaluation of the number of diseased cells and their vitality. 将不同体积的样品(lyL、3yL、5yL和7yL) —式两份地等分至96孔平板中。 Different volumes of the sample (lyL, 3yL, 5yL and 7yL) - aliquoted in duplicate to a 96 well plate. 为了溶解红血球,将180yL氯化铵溶解溶液加入每个孔(2g KHC03、16.58g NH4Cl、0.074g Na2EDTA·2H20、H20至lL)。 In order to dissolve red blood cells, the 180yL ammonium chloride solution was added to each well to dissolve (2g KHC03,16.58g NH4Cl, 0.074g Na2EDTA · 2H20, H20 to lL). 在4°C下10分钟孵育期后,将平板在1200rpm下离心5分钟并移出上清液。 After 10 minutes of incubation at 4 ° C, the plates were centrifuged at 1200rpm for 5 minutes and the supernatant removed. 溶解步骤进行两次。 Dissolving step is performed twice. 为了进行分析,将20yL膜联蛋白V-FITC (Immunostep,Salamanca,Spain)、结合缓冲液(BB、2 · 4g HEPES、8.19g NaCl、0.37g CaCl2、H20至1L)和以下单克隆抗体(mAb)的组合加入每个孔: CD117 (克隆104D2) -PE (Becton Dickinson,San Jose,CA,US)、CD34 (克隆581) -PerCP (BioLegend,San Diego,CA,US)、HLADR (克隆L243) -PB (BioLegend)和CD45 (HI30) -PO (Life Technologies,Carlsbad,CA,US) (van Dongen,JJ^EuroFlow antibody panels for standardized n-dimensional flow cytometric immunophenotyping of normal, reactive and malignant leukocytes,Leukemia,2012,26,1908_75)。 For analysis, the 20yL Annexin V-FITC (Immunostep, Salamanca, Spain), binding buffer (BB, 2 · 4g HEPES, 8.19g NaCl, 0.37g CaCl2, H20 to 1L), and the monoclonal antibody (mAb ) is added to each well in combination: CD117 (clone 104D2) -PE (Becton Dickinson, San Jose, CA, US), CD34 (clone 581) -PerCP (BioLegend, San Diego, CA, US), HLADR (clone L243) -PB (BioLegend) and CD45 (HI30) -PO (Life Technologies, Carlsbad, CA, US) (van Dongen, JJ ^ EuroFlow antibody panels for standardized n-dimensional flow cytometric immunophenotyping of normal, reactive and malignant leukocytes, Leukemia, 2012 , 26,1908_75). 在室温下在黑暗中孵育15分钟后,使用结合缓冲溶液进行洗涤步骤。 After incubation in the dark at room temperature for 15 minutes using a binding buffer solution washing step. 使球粒再悬浮在30yL BB中,以供在Vivia' s Exvrredi©平台中进行分析。 In that the pellet was resuspended in 30yL BB, for use in Vivia 's Exvrredi © internet for analysis. 计算到达时的细胞数和活力,并且确定每孔使用的最佳样品体积。 Calculate cell number and viability arrival time, and determining the optimal sample volume used per well.

[0352] 在一个实施方案中,根据以下方法进行测定:将整个样品用补无有20 % (v/v) FBS (Thermo Scientific,Wal tham,MA,US)、2 %HEPES、I % 抗生素(Zell Shie Id, Labc linics, Barcelona,Spain)和I %L-谷氨酰胺200mM (Lonza,Hopkinton,MA,US)的RPMI 1640稀释,最终每孔体积是60yL。 [0352] In one embodiment, according to the following method of measurement: The entire sample fill No Yes 20% (v / v) FBS (Thermo Scientific, Wal tham, MA, US), 2% HEPES, I% antibiotics ( Zell Shie Id, Labc linics, Barcelona, ​​Spain) and diluted with I% L- glutamine 200mM (Lonza, Hopkinton, MA, US) in RPMI 1640, final volume per well is 60yL. 用Multidrop Combi Smart (Thermo Scientific Waltham,MA,US)将混合物分配至含有本文所述的化合物的96孔平板中。 Compound 96 Multidrop Combi Smart (Thermo Scientific Waltham, MA, US) assigned to the mixture containing the plates described herein. 预先使用Echo 550液体处理机(LabCyte,Sunnyvale,CA,US)准备药物平板。 Echo 550 in advance using a liquid handler (LabCyte, Sunnyvale, CA, US) preparing a pharmaceutical tablet. 每种测试化合物使用五种或八种浓度,对浓度进行调整以覆盖患者间活性的范围。 Each test compound concentration using five or eight kinds, concentration is adjusted to the range of coverage between patient activity. 还对测试化合物测试作为对照物的对应母体化合物。 Test compounds were tested as also the corresponding parent compound controls. 将平板在含有5 % CO2的湿润空气中在37 °C下孵育48小时。 The plates were incubated for 48 hours at 37 ° C for in a humidified atmosphere containing 5% CO2 in. ] 在一个实施方案中,用Summit软件(Beckman Coulter)进行数据分析。 ] In one embodiment, the data analyzed using Summit Software (Beckman Coulter). 使用门控策略,基于FSC/SSC和不同mAb标记物的表达或表达缺乏来鉴别病态细胞。 Gating strategy, based on the expression or expression of FSC / SSC different mAb and lack markers to identify diseased cells. 消减测量为在具有本文所述的化合物的孔中对比没有化合物的对照孔中活细胞数目的差异。 Measured as the reduction of the number of comparison in control wells without compound difference viable cells in the wells having the compound herein. 接着使用膜联蛋白V排除濒死细胞并仅仅测量药物孔中和对照孔中活细胞的数目。 Then using Annexin V negative number of dying cells and the drug control wells and wells viable cells measure only. 没有膜联蛋白V染色和适当FSC/SSC的那些细胞被认为是活细胞(Koopman,G.等人,Annexin V for flow cytometric detection of phosphatidyl serine expression on B cells undergoing apoptosis,Blood,1994,84,1415-20)。 Those cells no annexin V staining and appropriate FSC / SSC are considered viable cells (Koopman, G. Et al., Annexin V for flow cytometric detection of phosphatidyl serine expression on B cells undergoing apoptosis, Blood, 1994,84,1415 -20). 使用以上参数,使用FCS分析器测定每种个别化合物的作用。 Using the above parameters, the effects of each individual compound was measured using the analyzer FCS. 数据转移至ActivityBase (IDBS,Guildford,UK)以便进行最终分析。 Transferring data to ActivityBase (IDBS, Guildford, UK) for the final analysis.

[0354] 可以根据本领域的技术人员已知的任何测定来测定化合物对肝癌的活性。 [0354] The active compounds can be determined according to any of the assays of liver skilled artisan.

[0355] 此外,可以根据本领域的技术人员已知的任何测定针对受试者的肝细胞中的累积来测定化合物。 [0355] Further, for the liver cells in a subject compound according to any of accumulation assay measured the skilled artisan. 在某些实施方案中,化合物可以施用于受试者,并且可以针对化合物或其衍生物,例如核苷、其磷酸核苷或三磷酸核苷衍生物,测定受试者的肝细胞。 In certain embodiments, the compound may be administered to a subject, and may be directed to compounds or derivatives thereof, e.g. nucleoside, nucleoside phosphate or its nucleoside triphosphate derivative, hepatocytes measured subject.

[0356] 在某些实施方案中,核苷化合物体内或体外施用于细胞,例如肝细胞,并测量细胞内递送的三磷酸核苷的水平,以指示细胞中化合物的递送和三磷酸化。 [0356] In certain embodiments, the nucleoside compound is administered to cells in vivo or in vitro, such as liver cells, and measuring the intracellular delivery of nucleoside triphosphates level to indicate the delivery of cells and triphosphate compounds. 可以使用本领域中已知的分析技术测量细胞内三磷酸核苷的水平。 Known in the art may be used analytical techniques for measuring intracellular nucleoside triphosphate levels. 下文举例描述检测ddATP的方法,但可以容易使用适当对照物、校准样品和测定技术检测其它三磷酸核苷。 Examples described hereinafter ddATP detection method, but can be easier to use appropriate controls, calibration samples and assay techniques to detect other nucleoside triphosphates.

[0357] 在某些实施方案中,通过与由对照样品制成的校准用标准比较,测量样品中的ddATP浓度。 [0357] In certain embodiments, by comparison with a control sample made from the calibration standard, the measurement ddATP concentration in the sample. 样品中的ddATP浓度可以使用例如HPLC LC MS等分析法测量。 ddATP concentration in the sample can be measured using methods such as HPLC LC MS analysis and the like. 在某些实施方案中,将测试样品与用已知浓度的ddATP产生的校准曲线相比,从而获得该样品的浓度。 In certain embodiments, the test sample compared with the calibration curve generated with known concentrations of ddATP, to thereby obtain the concentration of the sample.

[0358] 在某些实施方案中,对样品进行操控以在分析前去除例如盐(Na+、K+等)等杂质。 [0358] In certain embodiments, the samples were manipulated to remove, for example, a salt (Na +, K +, etc.) and other impurities prior to analysis. 在某些实施方案中,肝细胞细胞提取物的定量下限是约〇.2pmol/mL,特别是在存在的盐减少的情况下。 In certain embodiments, the hepatocyte cell extract were lower limit of quantitation was about 〇.2pmol / mL, especially in the presence of a salt reduction.

[0359] 在某些实施方案中,所述方法允许成功地测量例如培养的肝细胞和HepG2细胞中形成的三磷酸核苷酸,在每百万细胞1-10,OOOpmol的水平下。 [0359] In certain embodiments, the method allows for measuring, for example successfully cultured hepatocytes and HepG2 cells formed triphosphate nucleotides, at 1-10, OOOpmol level per million cells.

[0360] 与其它治疗剂组合 [0360] in combination with other therapeutic agents

[0361] 在一个实施方案中,是包含如本文所述的化合物,例如式I-VIII的化合物或其药学上可接受的盐以及一种、两种、三种或更多种其它治疗剂,例如抗癌剂的组合。 [0361] In one embodiment, a compound as described herein comprises, for example, a compound of formula I-VIII, or a pharmaceutically acceptable salt thereof and one, two, three or more other therapeutic agents, for example, a combination of anticancer agents.

[0362] 在某些实施方案中,本文提供的化合物和组合物可用于治疗癌症的方法中,所述方法包括进一步施用有效治疗有需要的受试者的癌症的第二药剂。 [0362] In certain embodiments, provided herein are compounds and compositions can be used in a method of treating cancer, said method further comprising administering a second agent effective to treat cancer in a subject in need of. 第二药剂可以是本领域的技术人员已知的有效治疗癌症的任何药剂,包括当前经FDA批准的药剂。 The second agent can be effectively known to those skilled in the art that any agents to treat cancer, including the current drug approved by the FDA. 在某些实施方案中,癌症选自肝癌、乳腺癌、卵巢癌、肺癌、胰腺癌或白血病癌。 In certain embodiments, the cancer is selected from cancer, breast cancer, ovarian cancer, lung cancer, pancreatic cancer or leukemia. 在一个实施方案中,癌症是肝癌。 In one embodiment, the cancer is liver cancer.

[0363] 在某些实施方案中,本文提供的化合物与一种第二药剂组合施用。 [0363] In certain embodiments, a compound provided herein is administered in combination with a second agent. 在其它实施方案中,本文提供的化合物与两种第二药剂组合施用。 In other embodiments, the second agent in combination with two kinds of compounds provided herein are administered. 在其它实施方案中,本文提供的化合物与两种或更多种第二药剂组合施用。 In other embodiments, the second agent in combination with two kinds of compounds provided herein or more administration.

[0364] 如本文所用,术语“组合”包括使用超过一种疗法(例如一种或多种预防剂和/或治疗剂)。 [0364] As used herein, the term "combination" includes the use of more than one therapy (e.g., one or more prophylactic and / or therapeutic agents). 术语“组合”的使用并不限制疗法(例如预防剂和/或治疗剂)施用于患有病症的受试者的次序。 The term "in combination" does not limit therapy (e.g., prophylactic and / or therapeutic agents) of the order of a subject suffering from a disorder administered. 第一疗法(例如预防剂或治疗剂,例如本文提供的化合物)可以在第二疗法(例如预防剂或治疗剂)施用于患有病症的受试者之前(例如5分钟、15分钟、30分钟、45分钟、1小时、2小时、4小时、6小时、12小时、24小时、48小时、72小时、96小时、1周、2周、3周、4周、5周、6 周、8周或12周前)、同时或之后(例如5分钟、15分钟、30分钟、45分钟、1小时、2小时、4小时、6 小时、12小时、24小时、48小时、72小时、96小时、1周、2周、3周、4周、5周、6周、8周或12周后) 施用。 Prior to the subject a first therapy (e.g., prophylactic or therapeutic agents, such as a compound provided herein) can be administered in the second treatment with the disorder (e.g., prophylactic or therapeutic agents) (e.g., 5 minutes, 15 minutes, 30 minutes 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concurrently, or after (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours , 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks) administration.

[0365] 如本文所用,术语“协同”包括本文提供的化合物与已经或当前正用于预防、管理或治疗病症的另一疗法(例如预防剂或治疗剂)的组合,此组合比所述疗法的累加效应更有效。 [0365] As used herein, the term "synergistic" includes a compound provided herein in combination with another therapy has been or is currently being used to prevent, manage or treat a disorder (e.g., prophylactic or therapeutic agent), the ratio of this combination therapy the cumulative effect is more effective. 疗法组合(例如预防剂或治疗剂的组合)的协同效应允许一种或多种疗法使用更低剂量和/或所述疗法施用于患有病症的受试者的频率更低。 Combination of therapies (e.g., a combination of prophylactic or therapeutic agents) allow the synergistic effect of one or more therapies using lower doses and / or the therapy administered to a subject suffering from the disorder a lower frequency of. 利用更低剂量的疗法(例如预防剂或治疗剂)和/或施用所述疗法的频率更低的能力降低了与所述疗法施用于受试者有关的毒性,而不会降低所述疗法预防或治疗病症的功效。 Use of lower dosages of therapies (e.g., prophylactic or therapeutic agents) and / or less frequent administration of said therapies ability to reduce toxicity associated with the therapy administered to a subject without reducing the preventive therapy or efficacy of the condition being treated. 另外,协同效应可以改善药剂预防或治疗病症的功效。 In addition, a synergistic effect can improve the effectiveness of drug prevention or treatment of a disorder. 最终,疗法组合(例如预防剂或治疗剂的组合)的协同效应可以避免或减少与使用单独疗法有关的不利或者不必要的副作用。 Finally, the combination of therapies (e.g., a combination of prophylactic or therapeutic agents) may avoid or reduce the synergistic effect with the use of a sole therapy or unnecessary adverse side effects associated.

[0366] 本文提供的活性化合物可以与另一治疗剂、尤其抗癌剂组合或交替施用。 [0366] The active compounds may be provided herein with another therapeutic agent, in particular an anticancer agent administered in combination or alternation. 在组合疗法中,有效剂量的两种或更多种药剂一起施用,而在交替或依次步骤疗法中,有效剂量的每种药剂连续或依次施用。 In combination therapy, administration of two or more agents together effective dose, whereas in alternation or sequential-step therapy, an effective dosage of each agent is administered sequentially or continuously. 所给的剂量将取决于药物的吸收、灭活和排泄率以及本领域的技术人员已知的其它因素。 The dose given will depend on absorption, inactivation, and excretion rates of the drug as well as other factors known to those skilled in the art. 应当注意剂量值还将随有待减轻的病状的严重度而变。 It should be noted that dosage values ​​will also be alleviated with the severity of symptoms vary. 进一步了解,对于任何特定的受试者来说,应根据个人需要和施用或监督组合物施用的人的专业判断,随时间调整特定的给药方案和时间表。 Further understood that for any particular subject, it should be based on individual needs and administering or supervising the administration of the compositions of the professional judgment of the person, to adjust the specific dosage regimens and schedules over time.

[0367] 在某些实施方案中,第二药剂选自下组,该组由以下各项组成:索拉非尼甲苯磺酸盐(sorafenib tosylate) (Nexavar)、放射疗法、选择性体内放射疗法(例如SIR-Spheres和TheraSphere)、乙鹏油(Lipidol)、派莫德维(pexastimogene devacirepvec) (Pexa-Vec、 JX_594、Jennarex)、喹B丫因(Quinacrine) (Clevelane BioLabs)、CC_223 (Celgene)、CF102 (Can-Fite)、SGI_110 (Astex)和G-202 (Genspera) 〇 [0367] In certain embodiments, the second agent is selected from the group consisting of: sorafenib tosylate (sorafenib tosylate) (Nexavar), radiation therapy, selective internal radiation therapy (e.g., SIR-Spheres and TheraSphere), Peng B oil (Lipidol), send Mode Wei (pexastimogene devacirepvec) (Pexa-Vec, JX_594, Jennarex), due quinolin B Ah (quinacrine) (Clevelane BioLabs), CC_223 (Celgene) , CF102 (Can-Fite), SGI_110 (Astex) and G-202 (Genspera) square

[0368] 在一个实施方案中,另一抗癌剂选自下组,该组由以下各项组成:血管内皮生长因子(vascular endothelial growth factor,VEGF)受体抑制剂、拓扑异构酶II抑制剂、平滑蛋白抑制剂(smoothen inhibitor)、烧基化剂、抗肿瘤抗生素、抗代谢药、类视黄醇、免疫调节剂,包括但不限于抗癌疫苗、CTLA-4、LAG-3、ro-l拮抗剂和BET布罗莫结构域抑制剂。 [0368] In one embodiment, the other anticancer agent is selected from the group consisting of: vascular endothelial growth factor (vascular endothelial growth factor, VEGF) receptor inhibitors, topoisomerase II inhibitors agents, smoothing inhibitors (smoothen inhibitor), burning alkylating agent, antitumor antibiotics, antimetabolites, retinoid, an immunomodulator, include but are not limited to anti-cancer vaccine, CTLA-4, LAG-3, ro -l antagonists and inhibitors BET bromodomain.

[0369] 血管内皮生长因子(VEGF)受体抑制剂的实例包括(但不限于)贝伐单抗(bevacizumab) (Genentech/Roche以商标AVASTIN出售)、阿西替尼(axitinib) (N-甲基_2_ [[3- [ ([E]) -2-吡啶-2-基乙烯基]-IH-吲唑-6-基]硫基]苯甲酰胺,又名AG013736,并描述在PCT公布No.WO 01/002369中)、丙氨酸布立尼布(Brivanib Alaninate)(⑸-(⑻-1-(4-(4-氟-2-甲基-IH-吲哚-5-基氧基)-5-甲基吡咯并[2,1-f] [1,2,4]三嗪-6-基氧基)丙-2-基)2-氨基丙酸酯,又名BMS-582664)、莫特沙芬(motesanib) (N- (2,3-二氢-3,3-二甲基- IH-吲哚-6-基)-2- [ (4-吡啶基甲基)氨基]-3-吡啶甲酰胺并描述在PCT公布No . WO 02/ 068470中)、帕瑞肽(pasireotide)(又名SO 230并描述在PCT公布No.WO 02/010192中)和索拉非尼(以商品名称NEXAVAR出售)。 [0369] Vascular endothelial growth factor (VEGF) receptor inhibitors Examples include (but are not limited to) Avastin (bevacizumab) (Genentech / Roche sold under the trademark AVASTIN), axitinib (axitinib) (N- methyl yl _2_ [[3- [([E]) -2- pyridin-2-yl ethenyl] -IH- indazol-6-yl] thio] benzamide, AG013736 known, and is described in PCT publication No.WO 01/002369), the alanine Briggs Technip (Brivanib Alaninate) (⑸- (⑻-1- (4- (4- fluoro-2-methyl-indol-5-yloxy -IH- yl) -5-methyl-pyrrolo [2,1-f] [1,2,4] triazin-6-yloxy) propan-2-yl) 2-propanoate, also known as BMS-582664 ), motexafin (motesanib) (N- (2,3- dihydro-3,3-dimethyl - IH- indol-6-yl) -2- [(4-pyridylmethyl) amino ] -3-pyridine-carboxamide and is described in publication No PCT. WO 02/068470), the pasireotide (pasireotide) (also known as SO 230 and described in PCT publication No.WO 02/010192), and sorafenib (sold under the trade name NEXAVAR).

[0370] 拓扑异构酶II抑制剂的实例包括但不限于依托泊苷(etoposide)(又名VP-16和依托泊苷磷酸盐,以商品名称T0P0SAR、VEPESID和ET0P0PH0S出售)和替尼泊苷(teniposide) (又名VM-26,以商品名称VUMON出售)。 [0370] Examples of topoisomerase II inhibitors include but are not limited to, etoposide (etoposide) (also known as VP-16 and etoposide phosphate, trade name T0P0SAR, VEPESID and sold ET0P0PH0S) and teniposide (teniposide) (also known as VM-26, sold under the trade name VUMON).

[0371] 烷基化剂的实例包括但不限于5-氮胞苷(5-azacytidine)(以商品名称VIDAZA出售)、地西他滨(decitabine)(以商品名称DE⑶GEN出售)、替莫卩坐胺(temoz〇Iomide) (Schering-Plough/Merck以商品名称TEM0DAR和TEM0DAL出售)、放线菌素D (dactinomycin) (又名放线菌素-D并以商品名称C0SMEGEN出售)、美法仑(melphalan)(又名L-PAM、L-溶肉瘤素和苯丙氨酸氮芥,以商品名称ALKERAN出售)、六甲蜜胺(altretamine)(又名六甲三聚氰胺(hexamethylmelamine,HMM),以商品名称HEXALEN出售)、卡莫司汀(carmustine)(以商品名称BCNU出售)、苯达莫司汀(bendamustine)(以商品名称TREANDA出售)、白消安(busulfan)(以商品名称Busulfex⑻和Myleran⑻出售)、卡铀(carboplatin)(以商品名称Paraplatin⑻出售)、洛莫司汀(Iomustine)(又名CCNU,以商品名称CeeNU⑻出售))、顺铂(cisplatin)(又名CDDP,以商品名称Platinol⑻和Platinol⑻-AQ出售)、苯 [0371] Examples of alkylating agents include, but are not limited to 5-azacytidine (5-azacytidine) (sold under the trade name of VIDAZA), decitabine (that decitabine) (sold under the trade name DE⑶GEN), temozolomide sit Jie amine (temoz〇Iomide) (Schering-Plough / Merck and sold under the trade name TEM0DAR TEM0DAL), actinomycin D (dactinomycin) (also known as actinomycin and sold under the trade name -D C0SMEGEN), melphalan ( melphalan) (also known as L-PAM, L- dissolved sarcoma and melphalan, sold under the trade name ALKERAN), hexamethylmelamine (altretamine) (also known as hexamethylmelamine (hexamethylmelamine, HMM), the trade name HEXALEN sold), carmustine (carmustine) (sold under the trade name BCNU), bendamustine (bendamustine) (sold under the trade name TREANDA), busulfan (busulfan) (trade name Busulfex⑻ and sold Myleran⑻), card uranium (carboplatin) (sold under the trade name Paraplatin⑻), lomustine (Iomustine) (also known as CCNU, sold under the trade name CeeNU⑻)), cisplatin (cisplatin) (also known as CDDP, under the trade name Platinol⑻ and Platinol⑻- AQ sale), phenyl 酸氮芥(chlorambucil)似商品名称Leukeran⑻出售)、环磷酰胺(cyclophosphamide)似商品名称〇}^(«&11(1?)和此〇8&1^1?)出售)、达卡巴嗪((1&〇&1^&2;[116)(又名01'1(]、01(]和咪卩坐甲酰胺, 以商品名称DTIC-Dome⑻出售)、六甲蜜胺(altretamine)(又名六甲三聚氰胺(HMM),以商品名称Hexalen⑻出售)、异环磷酰胺(ifosfamide)(以商品名称Ifex⑻出售)、丙卡巴肼(procarbazine)(以商品名称Matulane ⑻出售)、氮芥(mechlorethamine)(又名氮芥(nitrogen mustard)、氮芥(mustine)和氮芥盐酸盐,以商品名称Mustargen (R)出售)、链脲霉素(streptozocin)(以商品名称Zanosar⑻出售)、噻替派(thiotepa)(又名硫代磷酰胺、 TESPA和TSPA,并以商品名称Thioplex⑻出售)。 Acid nitrogen mustards (chlorambucil) Leukeran⑻ sell similar goods name), cyclophosphamide (cyclophosphamide) like tradename square} ^ ( «& amp; 11 (1?) And this 〇8 & amp;? 1 ^ 1) Sold), dacarbazine ((1 & amp; square & amp; 1 ^ & amp; 2; [116) (also known as 01'1 (], 01 (] and the microphone Jie sit carboxamide, tradename DTIC-Dome⑻ sold), hexamethylmelamine (altretamine) (aka Rokko melamine (HMM), sold under the trade name Hexalen⑻), ifosfamide (ifosfamide) (Ifex⑻ sold under the trade name), procarbazine (procarbazine) (sold under the trade name Matulane ⑻), nitrogen mustard (mechlorethamine ) (also known as mechlorethamine (nitrogen mustard), chlorambucil (mustine) and mechlorethamine hydrochloride, sold under the trade name Mustargen (R)), streptozotocin (streptozocin) (sold under the trade name Zanosar⑻), thiotepa send (thiotepa) (also known as Thiophosphoramides, TESPA and TSPA, and sold under the trade name Thioplex⑻).

[0372] 抗肿瘤抗生素的实例包括(但不限于)多柔比星(doxorubicin)(以商品名称Adriamycin⑻和Rubex⑻出售)、博莱霉素(bleomycin)(以商品名称Ienoxane⑻出售)、 道诺霉素(daunorubicin)(又名道诺霉素盐酸盐、道诺霉素(daunomycin)和柔红霉素盐酸盐,以商品名称Cerubidine⑻出售)、道诺霉素脂质体(daunorubicin liposomal)(道诺霉素朽1檬酸盐脂质体,以商品名称DaunoXome⑻出售)、米托蒽醌(mitoxantrone)(又名DHAD, 以商品名称Novantrone (R)出售)、表柔比星(epirubicin)(以商品名称Ellence (TM)出售)、 伊达比星(idarubicin)(以商品名称Idamycin⑻、Idamycin PFS (R)出售)和丝裂霉素C (mitomycin C)(以商品名称Mutamycin⑻出售)。 [0372] Examples of antitumor antibiotics include (but are not limited to) doxorubicin (doxorubicin) (sold under the trade name Adriamycin⑻ and Rubex⑻), bleomycin (bleomycin) (sold under the trade name Ienoxane⑻), daunorubicin (daunorubicin) (also known as daunorubicin hydrochloride, daunorubicin (daunomycin) and daunorubicin hydrochloride, sold under the trade name Cerubidine⑻), daunorubicin liposomal (daunorubicin liposomal) (Road daunorubicin liposomal rotten a citric acid salt, sold under the trade name DaunoXome⑻), mitoxantrone (mitoxantrone) (of DHAD known under the trade name Novantrone (R) sold), epirubicin (epirubicin) (in tradename Ellence (TM) sold), idarubicin (idarubicin) (trade name Idamycin⑻, Idamycin PFS (R) sold) and mitomycin C (mitomycin C) (sold under the trade name Mutamycin⑻).

[0373] 抗代谢药的实例包括(但不限于)克拉屈滨(claribine) (2-氯去氧基腺苷,以商品名称Ieustatin⑻出售)、5_氟尿喃啶(5-fluorouracil)(以商品名称Adrucil⑻出售)、6_ 硫代鸟噪呤(6-thioguanine)(以商品名称Purinethol⑻出售)、培美曲塞(pemetrexed) (以商品名称Alimta (R)出售)、阿糖胞苷(又名阿糖胞喃啶(Ara-C),以商品名称Cytosar-U ⑻出售)、阿糖胞苷脂质体(又名Liposomal Ara-C,以商品名称DepoCyt (TM)出售)、地西他滨(decitabine)(以商品名称Dacogen⑻出售)、轻基脲(hydroxyurea)(以商品名称Hydrea ⑻、Droxia (TM)和Mylocel (TM)出售)、氟达拉滨(f Iudarabine)(以商品名称Fludara⑻出售)、氟尿苷(floxuridine)似商品名称FUDR⑻出售)、克拉屈滨(又名2-氯去氧基腺苷(2-CdA),以商品名称Leustatin (TM)出售)、氨甲蝶呤(methotrexate)(又名氨甲蝶呤、氨甲蝶呤钠(MTX),以商品名称Rheumatrex (R)和Trexall (TM))出售 Examples [0373] antimetabolites include (but are not limited to) cladribine (claribine) (2- chloro group to adenosine, sold under the trade name Ieustatin⑻), 5_ fluorouracil thiopyran piperidine (5-fluorouracil) (in product name Adrucil⑻ sold), 6_ thiosulfate birds noise methotrexate (6-thioguanine) (sold under the trade name Purinethol⑻), pemetrexed (pemetrexed) (under the trade name Alimta (R) sold), cytarabine (also known as Ara furans pyridine (Ara-C), sold under the trade name Cytosar-U ⑻), cytarabine liposome (aka liposomal Ara-C, under the trade name DepoCyt (TM) sold), decitabine (that decitabine) (sold under the trade name Dacogen⑻), urea light (of hydroxyurea) (trade name Hydrea ⑻, Droxia (TM) and Mylocel (TM) sold), fludarabine (f Iudarabine) (sold under the trade name Fludara⑻ ), floxuridine (floxuridine) sold FUDR⑻ like tradename), cladribine (2-chloro-known group to adenosine (2-CdA), sold under the trade name Leustatin (TM)), methotrexate ( methotrexate) (also known as methotrexate, methotrexate sodium methotrexate (of MTX), the trade name Rheumatrex (R) and Trexall (TM)) sold 和喷司他丁(pentostatin) (以商品名称Nipent⑻出售)。 And pentostatin (pentostatin) (sold under the trade name Nipent⑻).

[0374] 类视黄醇的实例包括(但不限于)阿利维A酸(a I i tre t ino iη)(以商品名称Panretin⑻出售)、维甲酸(tretinoin)(全反式视黄酸,又名ATRA,以商品名称Vesanoid ⑻出售)、异维甲酸(Isotretinoin) (13-c/s-视黄酸,以商品名称Accutane⑻、Amnesteem (R)、Claravis (R)、Clarus (R)、Decutan (R)、Isotane (R)、Izotech (R)、0ratane (R)、Isotret ⑻和Sotret⑻出售)和贝沙罗汀(bexarotene)(以商品名称Targretin⑻出售)。 [0374] Examples of retinoids include classes (but not limited to) Liwei A acid (a I i tre t ino iη) (sold under the trade name Panretin⑻), retinoic acid (as tretinoin) (all-trans retinoic acid, and name of ATRA, sold under the trade name Vesanoid ⑻), isotretinoin (isotretinoin) (13-c / s- retinoic acid, under the trade name Accutane⑻, Amnesteem (R), Claravis (R), Clarus (R), Decutan ( R), Isotane (R), Izotech (R), 0ratane (R), Isotret ⑻ and Sotret⑻ sold) and bexarotene (bexarotene) (sold under the trade name Targretin⑻).

[0375] “PD-1拮抗剂”意指阻断在癌细胞上表达的PD-Ll与在免疫细胞(T细胞、B细胞或NKT细胞)上表达的ro-i的结合并且优选还阻断在癌细胞上表达的ro-L2与免疫细胞表达的PD-I的结合的任何化合物或生物分子。 [0375] "PD-1 antagonist" means a block in expressing cancer cells PD-Ll binding ro-i is expressed on immune cells (T cells, B cells or NKT cells) and preferably also block any compound or biomolecule ro-L2 expression expressed on the cancer cells and immune cells of PD-I binding. PD-I和其配体的替代名称或同义词包括:PD-1是PDCDl、PD1、CD279和SLEB2;PD-Ll是PDCD1L1、PDL1、B7H1、B7-4、CD274和B7-H;以及PD-L2是?0〇011^、? Alternative names PD-I and its ligands or synonyms comprising: PD1 is PDCDl, PD1, CD279 and SLEB2; PD-Ll is PDCD1L1, PDL1, B7H1, B7-4, CD274, and B7-H; and PD-L2 yes? 0〇011 ^ ,? 01^、87-0(:、8七(1(3和^273。在其中正治疗人类个体的本发明的任何治疗方法、药剂和用途中,PD-I拮抗剂阻断人类PD-Li与人类ro-i的结合,并且优选阻断人类ro-Li和ro-L2与人类PD-I的结合。人类PD-I氨基酸序列可以在NCBI位置No. :NP_005009中找到。人类PD-Ll和H)-L2氨基酸序列可以分别在NCBI位置No.: NP_054862和NP_079515中找到。 01 ^, 87-0 (:, 8 VII (1 (3 ^ 273 and in the treatment of the present invention wherein any human subject being treated methods, and uses an agent, PD-I antagonists and human PD-Li human binding ro-i, and preferably block the binding of human ro-Li and ro-L2 to human PD-I is the amino acid sequence of human PD-I can be in the NCBI position No.:. NP_005009 found human PD-Ll and H. ) -L2, amino acid sequences may each position No .: NP_054862 in the NCBI and NP_079515 found.

[0376] 可用于本发明的任何治疗方法、药剂和用途中的PD-I拮抗剂包括特异性结合于ro-i或PD-Ll并且优选地特异性结合于人类ro-i或人类PD-Ll的单克隆抗体(mAb)或其抗原结合片段。 [0376] may be any of the therapeutic methods of the invention for use in the pharmaceutical and PD-I antagonists include ro-i specifically binds to PD-Ll, or preferably and specifically bind to a human ro-i or human PD-Ll monoclonal antibody (mAb) or an antigen binding fragment thereof. mAb可以是人类抗体、人源化抗体或嵌合抗体,并且可以包括人类恒定区。 mAb antibody may be a human, humanized or chimeric antibodies, and may include a human constant region. 在一些实施方案中,人类恒定区选自下组,该组由以下各项组成:]^61、]^62、]^63和]^64,并且在优选实施方案中,人类恒定区是IgGl或IgG4恒定区。 In some embodiments, the human constant region is selected from the group consisting of:] 61 ^,] 62 ^,] and 63 ^] ^ 64, and in a preferred embodiment, the human constant region is IgGl or IgG4 constant region. 在一些实施方案中,抗原结合片段选自下组,该组由以下各项组成:? In some embodiments, the antigen binding fragment is selected from the group consisting of:? 813、? 813 ,? 313/-3!1、? 313 / -3! 1 ,? (313/)2、80?¥和?¥片段。 (313 /) 2,80? ¥ and? ¥ fragments.

[0377] 结合于人类PD-I并且可用于本发明的治疗方法、药剂和用途的mAb的实例描述于US7488802、US7521051、US8008449、US8354509、US8168757、W02004/004771、W02004/ 072286、W02004/056875和US201I/0271358中。 [0377] binding to human PD-I and may be used Examples of mAb treatment method of the present invention, an agent and use are described in US7488802, US7521051, US8008449, US8354509, US8168757, W02004 / 004771, W02004 / 072286, W02004 / 056875 and US201I / 0271358 in.

[0378] 结合于人类H)-L1并且可用于本发明的治疗方法、药剂和用途的mAb的实例描述于W02013/019906、W02010/077634 Al和US8383796中。 [0378] bound to human H) -L1 and may be used Examples of mAb treatment method of the present invention, and pharmaceutical uses are described in W02013 / 019906, W02010 / 077634 Al and in US8383796. 在本发明的治疗方法、药剂和用途中可用作PD-I拮抗剂的特定抗人类PD-Ll mAb包括MPDL3280A、BMS-936559、MEDI4736、 MSB0010718C和W02013/019906的分别包含SEQIDN0:24和SEQIDN0:21的重链和轻链可变区的抗体。 PD-I antagonists useful in the treatment method of the present invention, an agent and uses a specific anti-human PD-Ll mAb comprises MPDL3280A, BMS-936559, MEDI4736, MSB0010718C and W02013 / 019906, respectively contain SEQIDN0: 24 and SEQIDN0: antibody heavy and light chain variable regions 21.

[0379] 可用于本发明的任何治疗方法、药剂和用途的其它PD-I拮抗剂包括特异性结合于ro-i或PD-Li并且优选地特异性结合于人类ro-i或人类ro-Li的免疫粘附素,例如含有与例如免疫球蛋白分子的Fc区的恒定区融合的PD-Ll或ro-L2的细胞外或PD-I结合部分的融合蛋白。 [0379] may be any of the therapeutic methods of the invention for pharmaceutical and other uses of antagonists include PD-I specific binding to ro-i or PD-Li and preferably bind specifically to a human or human ro-i ro-Li immunoadhesin, such a fusion protein binds to the constant region of an outer e.g. Fc region of an immunoglobulin molecule fused to PD-Ll or ro-L2 or PD-I cells with the portion. 特异性结合于PD-I的免疫粘附素分子的实例描述于W02010/027827和W02011/ 066342。 Examples of an immunoadhesin molecule specifically binds to PD-I is described in W02010 / 027827 and W02011 / 066342. 在本发明的治疗方法、药剂和用途中可用作PD-I拮抗剂的特定融合蛋白包括AMP-224 (又名B7-DCIg),它是ro-L2-FC融合蛋白并结合于人类Η)-1。 PD-I antagonists useful in the treatment method of the present invention, an agent and uses a specific fusion protein comprises AMP-224 (also known as B7-DCIg), which is ro-L2-FC fusion protein and binding to the human [eta]) -1.

[0380] 其它细胞毒性剂的实例包括(但不限于)三氧化二砷(以商品名称Trisenox (R)出售)、天冬酰胺酶(又名L-天冬酰胺酶和欧文氏菌属L-天冬酰胺酶,以商品名称Elspar⑻和Kidrolase ⑻出售)。 [0380] Other examples of cytotoxic agents include (but are not limited to) trioxide (sold under the trade name Trisenox (R)), asparaginase (L- asparaginase known and Erwinia L- asparagine enzyme, sold under the trade name Elspar⑻ and Kidrolase ⑻).

[0381] 在一个实施方案中,另一抗癌剂是BET布罗莫结构域抑制剂。 [0381] In one embodiment, the other anticancer agent is an inhibitor BET bromodomain. BET布罗莫结构域抑制剂的实例包括美国专利N〇.5712274、W01994006802、美国专利化.8476260和卵2009/ 084693中描述的化合物。 Examples BET bromodomain inhibitors include compounds described in US Patent No. N〇.5712274, W01994006802, and U.S. Patent No. of eggs .8476260 2009/084693 described. 实施例 Example

[0382] 如本文所用,用于这些方法、方案和实施例中的符号和约定都与同时代的科学文南犬,例如the Journal of the American Chemical Society或the Journal of Biological Chemistry中所用的符号和约定一致,不管是否特定地定义具体的缩写。 [0382] As used herein, used in these processes, schemes and examples of the symbols and conventions are the contemporary scientific Wennan dogs, for example the Journal of the American Chemical Society or the Journal symbol of Biological Chemistry used and agreed unanimously, regardless of whether a particular defined specific abbreviations. 具体来说,但不限制,以下缩写可以用于实施例和通篇说明书中:g(克);mg (毫克);mL (毫升) (微升);11^(毫摩尔浓度)^1(微摩尔浓度);抱(赫兹);10^(兆赫);111111〇1(毫摩尔);1^或11^ (小时);min (分钟);MS (质谱分析法);ESI (电喷雾电离);TLC (薄层色谱法);HPLC (高压液相色谱法);THF (四氢呋喃);CDC13(氖化氯仿);AcOH (乙酸);DCM (二氯甲烷);DMS0(二甲亚砜);DMS〇-d6 (氖化二甲亚砜);EtOAc (乙酸乙酯);MeOH (甲醇);BOC (叔丁基羰基);DMTr (4, 4二甲氧基三苯甲基);和MMTr (二甲氧基三苯甲基)。 In particular, but not limited to, the following abbreviations may be used in the examples and throughout the specification: g (grams); mg (milligrams); mL (milliliters) (l); ^ (millimolar concentrations) 11 ^ 1 ( micromolar); hold (Hz); 10 ^ (MHz); 111111〇1 (millimolar); or ^ 11 ^ 1 (hours); min (minutes); MS (mass spectrometry); ESI (electrospray ionization ); TLC (thin layer chromatography); HPLC (high pressure liquid chromatography); of THF (tetrahydrofuran); CDCl3 (chloroform Ne); of AcOH (acetic acid); DCM (dichloromethane); DMSO (dimethylsulfoxide) ; DMS〇-d6 (dimethylsulfoxide Ne); EtOAc in (ethyl acetate); MeOH (methanol); the BOC (tert-butylcarbonyl); DMTr (4, 4-dimethoxytrityl); and MMTr (dimethoxytrityl).

[0383] 对于所有以下实施例,可以利用本领域的技术人员已知的标准处理和纯化方法。 [0383] For all the following embodiments may be utilized known to those skilled in the art of standard processing and purification methods. 除非另外指示,否则所有温度都用°c (摄氏度)表述。 Unless otherwise indicated, all temperatures are used ° c (degrees Celsius) expression. 除非另作说明,否则所有反应都在室温下进行。 Unless otherwise noted, all reactions were performed at room temperature. 本文中说明的合成方法论意图通过使用特定的实施例例示适用的化学,且并不指示本公开的范围。 The synthesis methodology described herein is intended by the use of specific chemical illustrated embodiment applicable and is not indicative of the scope of the present disclosure.

[0384] 方案1:制备试剂Bl至B6 [0384] Scheme 1: Preparation of Reagent Bl to B6

[0385] [0385]

Figure CN108368147AD00511

[0386] 试剂BI-B6根据方案1和以下通用程序A来合成。 [0386] BI-B6 reagent synthesized according to the following Scheme 1 and general procedure A.

[0387] 程序A [0387] Procedure A

[0388] 向搅拌的二氯磷酸4-硝基苯酯(12.03mmol)于DCM(5mL/mmol)中的溶液中加入对应醇溶液(I2.03mmo 1)。 [0388] To a stirred solution of dichloro acid 4-nitrophenyl ester (12.03 mmol) in DCM (5mL / mmol) was added a solution of the corresponding alcohol (I2.03mmo 1) in a solution. 将反应混合物在-78°C下进行搅拌并在-78°C下经10分钟时间加入三乙胺(13.23mmol)。 The reaction mixture was stirred at -78 ° C and over 10 minutes at -78 ° C was added triethylamine (13.23mmol). 将反应混合物在-78°C下搅拌30分钟。 The reaction mixture was stirred at -78 ° C 30 min. 接着在(TC下加入对应胺(12.03mmol)于DCM (2mL/mmol)中的溶液,然后经15分钟时间加入三乙胺(25.26mmol)。将反应混合物在〇°C下搅拌1小时并在室温下搅拌1小时,并且接着在减压下浓缩。将粗残余物用乙酸乙酯处理并滤去所得固体。滤液在减压下浓缩。粗化合物通过硅胶快速色谱法(PE/乙酸乙酯:5至40%)纯化,得到所期望的化合物。 Followed by addition of the corresponding amine (the TC (12.03mmol) in DCM (2mL / mmol) was then added over 15 minutes, triethylamine (25.26mmol). The reaction mixture was stirred for 1 hour at square ° C and was stirred at room temperature for 1 hour, and then concentrated under reduced pressure and the crude residue was treated with ethyl acetate and the resulting solid was filtered off and the filtrate was concentrated under reduced pressure and the crude compound purified by silica gel flash chromatography (PE / ethyl acetate...: 5 to 40%) to give the desired compound.

[0389] 试剂Bl: (2S) -2- [[ (4-硝基苯氧基)_苯氧基-磷酰基]氨基]丙酸异丙酯: [0389] Reagents Bl: (2S) -2- [[(4- nitrophenoxy) phenoxy _ - phosphoryl] amino] propanoate:

[0390] MS (ESI) m/z = 409 (MH+)。 [0390] MS (ESI) m / z = 409 (MH +).

[0391] 试剂B2: (2S)-2-[ [ (2-乙氧基-2-氧代基-乙氧基)-(4-硝基苯氧基)磷酰基]氨基]-4-甲基-戊酸乙酯:MS(ESI)m/z = 447.1 (MH+)。 [0391] Reagents B2: (2S) -2- [[(2- ethoxy-2-oxo - ethoxy) - (4-nitrophenoxy) phosphoryl] amino] -4- yl - pentanoic acid ethyl ester: MS (ESI) m / z = 447.1 (MH +).

[0392] 试剂B3: N-[(5-硝基-2-呋喃基)甲氧基-(4-硝基苯氧基)磷酰基]-1-苯基-甲胺: MS (ESI) m/z = 432.2 (MH_)。 [0392] Reagents B3: N - [(5- nitro-2-furyl) methoxy - (4-nitrophenoxy) phosphoryl] -1-phenyl - methanamine: MS (ESI) m / z = 432.2 (MH_).

[0393] 试剂B4: (2S)-2-[ [(2-甲氧基-2-氧代基-乙氧基)-(4-硝基苯氧基)磷酰基]氨基]-4-甲基-戊酸甲酯:MS (ESI) m/z = 419.0 (MH+)。 [0393] Reagents B4: (2S) -2- [[(2- methoxy-2-oxo - ethoxy) - (4-nitrophenoxy) phosphoryl] amino] -4- yl - pentanoic acid methyl ester: MS (ESI) m / z = 419.0 (MH +).

[0394] 试剂B5:N-[2-(叔丁基二硫基)乙氧基-(4-硝基苯氧基)磷酰基]-1-苯基-甲胺:MS (ESI)m/z = 457.2 (MH+)。 [0394] Reagents B5: N- [2- (tert-butylthio) ethoxy - (4-nitrophenoxy) phosphoryl] -1-phenyl - methanamine: MS (ESI) m / z = 457.2 (MH +).

[0395] 试剂B6:N-[ (3-甲基-2-硝基-咪唑-4-基)甲氧基-(4-硝基苯氧基)磷酰基]-1-苯基-甲胺:MS (ESI) m/z = 448.0(MH+)。 [0395] Reagents B6: N- [(3- methyl-2-nitro - imidazol-4-yl) methoxy - (4-nitrophenoxy) phosphoryl] -1-phenyl - methanamine : MS (ESI) m / z = 448.0 (MH +).

[0396] 方案2:制备化合物l〇lb、102b、103、104b、105、106和107 [0396] Scheme 2: Preparation of Compound l〇lb, 102b, 103,104b, 105,106, and 107

[0397] 化合物101b、102b、103、104b、105和106根据方案2和以下通用程序B来合成。 [0397] Compound 101b, 102b, 103,104b, 105 and 106 are synthesized according to the following Scheme 2 and general procedure B.

[0398] [0398]

Figure CN108368147AD00531

[0399] 程序B [0399] Procedure B

[0400] 在0°C下向化合物Al (37.8mmol)于卩比啶(7mL/mmol)中的溶液加入氯三甲基娃烧(226.8mmol)。 [0400] added to a solution of compound Al (37.8mmol) of pyridine in Jie (7mL / mmol) at 0 ° C for burning baby chlorotrimethylsilane (226.8mmol). 将反应混合物在室温下搅拌1小时并接着在室温下加入4-二甲基氨基吡啶(37.8mmo 1)和4,4' -二甲氧基三苯甲基氯(56.7mmo 1)。 The reaction mixture was stirred for 1 hour at room temperature and then added 4-dimethylaminopyridine (37.8mmo 1) and 4, 4 'at room temperature - dimethoxytrityl chloride (56.7mmo 1). 将反应混合物在50 °C下搅拌过夜并接着冷却至室温。 The reaction mixture was stirred at 50 ° C for overnight and then cooled to room temperature. 加入饱和NaHCO3水溶液并将反应混合物用DCM萃取两次。 Saturated aqueous NaHCO3 was added and the reaction mixture was extracted twice with DCM. 将合并的有机层干燥,在减压下浓缩并与甲苯共同蒸发,得到所期望的粗中间体。 The combined organic layer was dried, concentrated and co-evaporated with toluene under reduced pressure to give the crude desired intermediate. 在室温下向搅拌的此中间体于甲醇(lOmL/mmol)中的溶液中加入氟化铵(189.0mm〇l)。 Was added ammonium fluoride (189.0mm〇l) To a stirred solution of this intermediate in methanol (lOmL / mmol) was at room temperature. 将反应混合物在室温下搅拌过夜,接着在70°C下搅拌2小时30分钟并接着冷却至室温并在减压下浓缩。 The reaction mixture was stirred overnight at room temperature, followed by stirring at 70 ° C 2 hours 30 minutes and then cooled to room temperature and concentrated under reduced pressure. 粗残余物通过硅胶快速色谱法(DCM/CH30H)纯化,得到所期望的化合物。 The crude residue was purified by flash chromatography on silica gel (DCM / CH30H) to give the desired compound.

[0401] 在(TC下向化合物A2 (1.78mmol)于THF (lOmL/mmol)中的溶液加入IM叔丁基氯化镁的THF溶液(3.73mmol)。将反应混合物在室温下搅拌1小时,并且接着冷却至0°C。加入含适当试剂Bl-6 (1.95mmol)的THF (lOmL/mmol),并且将反应混合物在0°C下搅拌1小时并在室温下搅拌过夜。将反应混合物用乙酸乙酯稀释并用饱和NH4Cl溶液、水和盐水洗涤。将合并的有机层干燥,过滤并在减压下浓缩。粗残余物通过二氧化硅快速色谱法(DCM/乙醇或DCM/甲醇)纯化,得到所期望的中间体; [0401] The reaction mixture was stirred (the TC of compound A2 (1.78mmol) was added IM in t-butyl chloride in THF (lOmL / mmol) solution in THF (3.73 mmol) at room temperature for 1 hour, and then was cooled to 0 ° C. Add the appropriate reagent containing Bl-6 (1.95mmol) in THF (lOmL / mmol), and the reaction mixture stirred for 1 hour at 0 ° C and stirred at room temperature overnight. the reaction mixture was diluted with ethyl acetate ester was diluted and washed with saturated NH4Cl solution, water and brine. the combined organic layers were dried, filtered and concentrated under reduced pressure. the crude residue was purified by flash chromatography on silica (DCM / ethanol or DCM / methanol) to give the the desired intermediate;

[0402] 在氮气下向此中间体(0.48mmol)于DCM (15mL/mmol)中的溶液加入三氟乙酸(0.8mL/mmo 1或7.2mmo 1)。 [0402] To a solution of this intermediate (0.48 mmol) in DCM (15mL / mmol) was added trifluoroacetic acid (0.8mL / mmo 1 or 7.2mmo 1) under nitrogen. 将反应混合物在室温下搅拌2小时。 The reaction mixture was stirred at room temperature for 2 hours. 反应由LC/MS监测。 The reaction by LC / MS. 反应混合物在减压下浓缩。 The reaction mixture was concentrated under reduced pressure. 粗残余物通过二氧化硅快速色谱法(DCM/乙醇或DCM/甲醇:0至20%),接着在一些情况下通过RP-18色谱法(H2(VCH3CN)纯化,得到呈固体状的呈非对映异构体混合物形式的所期望的化合物。此混合物通过MS-制备型HPLC或通过手性HPLC纯化,得到2种呈纯固体化合物形式的所期望的非对映异构体。 Non was then purified by RP-18 chromatography (H2 (VCH3CN) in some cases, give as a solid: The crude residue was purified by flash chromatography on silica (0 to 20% DCM / ethanol or DCM / methanol) of the desired compound in the form of a mixture of enantiomers. the mixture was purified by chiral HPLC to give two kinds of the compounds in pure solid form of the desired diastereomeric isomers by preparative HPLC or MS-.

[0403] 实施例1 [0403] Example 1

[0404] (化合物10 Ib) [0404] (Compound 10 Ib)

[0405] (25)-2-[[[(2尺,35,45,5!0-5-(4-氨基-2-氧代基-嘧啶-1-基)-3,4-二羟基-四氢噻吩-2-基]甲氧基-苯氧基-磷酰基]氨基]丙酸异丙酯 [0405] (25) -2 - [[[(2 feet, 35,45,5 0-5- (4-amino-2-yl! - 1-yl) -3,4-dihydroxy - tetrahydro-thiophen-2-yl] methoxy - phenoxy - phosphoryl] amino] propanoate

[0406 [0406

Figure CN108368147AD00541

[0407] 化合物IOlb根据方案2和通用程序B,利用试剂Bl来合成。 [0407] The compound IOlb Scheme 2 and general procedure B, using reagent synthesized Bl.

[0408] 化合物IOlb (非对映异构体1):白色固体;1H NMR(DMS0-d6,400MHz) δ (ppm) 7.90 (d, J = 7.55Hz,lH),7.39-7.35 (m,2H),7.20-7.16(m,4H),7.08(brs,lH),6.45(d,J = 4.95Hz, 1H),6.00(dd,J=12.87Hz和10.02Hz,lH),5.81 (brs,lH),5.69(d,J = 7.55Hz,lH),5.63 (brs,lH),4.86(七重峰,J = 6.31Hz,lH),4·47-4·41 (m,lH),4.26-4.20 (m,lH),4·10-4·08 (m,lH),4·02-4·00 (m,lH),3·82-3·72 (m,lH),3·45-3·40 (m,lH),1·21 (d,J = 7.05Hz,3H), I · 165 (d,J = 6 · 31Hz,3H),I · 16 (d,J = 6 · 31Hz,3H) ; 31P 匪R (DMS〇-d6,162MHz) δ (ppm) 3 · 28 (s,lP) ;MS(ESI)m/z = 529.0(MH+) 〇 [0408] Compound iolB (diastereomer 1): white solid; 1H NMR (DMS0-d6,400MHz) δ (ppm) 7.90 (d, J = 7.55Hz, lH), 7.39-7.35 (m, 2H ), 7.20-7.16 (m, 4H), 7.08 (brs, lH), 6.45 (d, J = 4.95Hz, 1H), 6.00 (dd, J = 12.87Hz and 10.02Hz, lH), 5.81 (brs, lH ), 5.69 (d, J = 7.55Hz, lH), 5.63 (brs, lH), 4.86 (septet, J = 6.31Hz, lH), 4 · 47-4 · 41 (m, lH), 4.26-4.20 (m, lH), 4 · 10-4 · 08 (m, lH), 4 · 02-4 · 00 (m, lH), 3 · 82-3 · 72 (m, lH), 3 · 45-3 · 40 (m, lH), 1 · 21 (d, J = 7.05Hz, 3H), I · 165 (d, J = 6 · 31Hz, 3H), I · 16 (d, J = 6 · 31Hz, 3H ); 31P bandit R (DMS〇-d6,162MHz) δ (ppm) 3 · 28 (s, lP); MS (ESI) m / z = 529.0 (MH +) square

[0409] 化合物101b (非对映异构体2):白色固体;1H NMR(DMS0-d6,400MHz) δ (ppm) 7.89 (d, J = 7.49Hz,lH),7.40-7.36 (m,2H),7.23-7.16(m,4H),7.08(brs,lH),6.46(d,J = 4.79Hz, 1H),6.01 (dd,J=13.26Hz和10.04Hz,lH),5.80(brs,lH),5.70(d,J = 7.49Hz,lH),5.58 (brs,lH),4.88(七重峰,J = 6.26Hz,lH) ,4.46-4.40 (m,lH) ,4.19-4.12 (m,lH) ,4.09-4.08 (m,lH),4·00-3·99 (m,lH),3·83-3·73 (m,lH),3·39-3·35 (m,lH),1.23 (d,J = 7.02Hz,3H), I · 18 (d,J = 6 · 33Hz,3H),I · 175 (d,J = 6 · 33Hz,3H) ; 31P 匪R (DMS〇-d6,162MHz) δ (ppm) 3 · 24 (s,lP) ;MS(ESI)m/z = 529.0(MH+) 〇 [0409] Compound 101b (Diastereomer 2): white solid; 1H NMR (DMS0-d6,400MHz) δ (ppm) 7.89 (d, J = 7.49Hz, lH), 7.40-7.36 (m, 2H ), 7.23-7.16 (m, 4H), 7.08 (brs, lH), 6.46 (d, J = 4.79Hz, 1H), 6.01 (dd, J = 13.26Hz and 10.04Hz, lH), 5.80 (brs, lH ), 5.70 (d, J = 7.49Hz, lH), 5.58 (brs, lH), 4.88 (septet, J = 6.26Hz, lH), 4.46-4.40 (m, lH), 4.19-4.12 (m, lH ), 4.09-4.08 (m, lH), 4 · 00-3 · 99 (m, lH), 3 · 83-3 · 73 (m, lH), 3 · 39-3 · 35 (m, lH), 1.23 (d, J = 7.02Hz, 3H), I · 18 (d, J = 6 · 33Hz, 3H), I · 175 (d, J = 6 · 33Hz, 3H); 31P bandit R (DMS〇-d6 , 162MHz) δ (ppm) 3 · 24 (s, lP); MS (ESI) m / z = 529.0 (MH +) square

[0410] 实施例2 [0410] Example 2

[0411] (化合物102b) [0411] (Compound 102b)

[0412] (25)-2-[[[(2尺,35,45,5!0-5-(4-氨基-2-氧代基-嘧啶-1-基)-3,4-二羟基-四氢噻吩-2-基]甲氧基-(2-乙氧基-2-氧代基-乙氧基)磷酰基]氨基]-4-甲基-戊酸乙酯 [0412] (25) -2 - [[[(2 feet, 35,45,5 0-5- (4-amino-2-yl! - 1-yl) -3,4-dihydroxy - tetrahydro-thiophen-2-yl] methoxy - (2-ethoxy-2-oxo-ethoxy) - phosphoryl] amino] -4-methyl - pentanoic acid ethyl ester

[0413 [0413

Figure CN108368147AD00551

[0414] 化合物102b根据方案2和通用程序B,利用试剂B2来合成。 [0414] compound 102b according to Scheme 2 and general procedure B, using reagent synthesized B2.

[0415]化合物l〇2b (非对映异构体1):白色固体;1H NMR(DMS0-d6,400MHz) δ (ppm) 7.89 (d, J = 7.50Hz,lH),7.17(brs,lH),7.08(brs,lH),6.45(d,J = 4.84Hz,lH),5.76(d,J = 5.15Hz,lH),5.71(d,J = 7.50Hz,lH),5.66(dd,J=12.94Hz*10.27Hz,lH),5.55(d,J = 3.87Hz,lH),4.49(d,J = 9.74Hz,lH),4.51-4.43(m,lH),4·37-4·31 (m,lH),4.16(q,J = 7.07Hz,2H),4.12-4.04(m,4H),4.00-3.97 (m,lH),3.76-3.67 (m,lH),3.38-3.36 (m,lH), 1.78-1.68 (m,lH),1.53-1.38 (m,2H),1.22(t,J = 7.07Hz,3H),1.20(t,J = 7.07Hz,3H), 0.90-0.86 (m,6H) ; 31P NMR (DMS〇-d6,162MHz) δ (ppm) 8.29 (s,IP) ; MS (ESI) m/z = 567.5 (MH +)。 [0415] Compound l〇2b (diastereomer 1): white solid; 1H NMR (DMS0-d6,400MHz) δ (ppm) 7.89 (d, J = 7.50Hz, lH), 7.17 (brs, lH ), 7.08 (brs, lH), 6.45 (d, J = 4.84Hz, lH), 5.76 (d, J = 5.15Hz, lH), 5.71 (d, J = 7.50Hz, lH), 5.66 (dd, J = 12.94Hz * 10.27Hz, lH), 5.55 (d, J = 3.87Hz, lH), 4.49 (d, J = 9.74Hz, lH), 4.51-4.43 (m, lH), 4 · 37-4 · 31 (m, lH), 4.16 (q, J = 7.07Hz, 2H), 4.12-4.04 (m, 4H), 4.00-3.97 (m, lH), 3.76-3.67 (m, lH), 3.38-3.36 (m , lH), 1.78-1.68 (m, lH), 1.53-1.38 (m, 2H), 1.22 (t, J = 7.07Hz, 3H), 1.20 (t, J = 7.07Hz, 3H), 0.90-0.86 ( m, 6H); 31P NMR (DMS〇-d6,162MHz) δ (ppm) 8.29 (s, IP); MS (ESI) m / z = 567.5 (MH +).

[0416]化合物l〇2b (非对映异构体2):白色固体;1H NMR(DMS0-d6,400MHz) δ (ppm) 7.90 (d, J = 7.45Hz,lH),7.17(brs,lH),7.08(brs,lH),6.46(d,J = 4.88Hz,lH),5.76(d,J = 5.06Hz,1H),5.71 (d,J = 7.54Hz,lH),5.67 (dd,J= 13.02Hz和10.20Hz,1H),5.57 (d,J = 3.94Hz,lH),4.51-4.42(m,2H),4.40-4.30 (m,lH),4.18-4.05(m,6H),4.01-3.97(m,lH), 3.72-3.63 (m,lH),3.40-3.36 (m,lH),1.74-1.67 (m,lH),1.53-1.38 (m,2H),1.22 (t,J = 7.06Hz,3H),1.19(t,J = 7.06Hz,3H),0.90-0.87 (m,6H) ;31P NMR(DMS0-d6,162MHz)S(ppm) 8 · 17 (s,IP) ; MS (ESI) m/z = 567.5 (MH+)。 [0416] Compound l〇2b (Diastereomer 2): white solid; 1H NMR (DMS0-d6,400MHz) δ (ppm) 7.90 (d, J = 7.45Hz, lH), 7.17 (brs, lH ), 7.08 (brs, lH), 6.46 (d, J = 4.88Hz, lH), 5.76 (d, J = 5.06Hz, 1H), 5.71 (d, J = 7.54Hz, lH), 5.67 (dd, J = 13.02Hz and 10.20Hz, 1H), 5.57 (d, J = 3.94Hz, lH), 4.51-4.42 (m, 2H), 4.40-4.30 (m, lH), 4.18-4.05 (m, 6H), 4.01 -3.97 (m, lH), 3.72-3.63 (m, lH), 3.40-3.36 (m, lH), 1.74-1.67 (m, lH), 1.53-1.38 (m, 2H), 1.22 (t, J = 7.06Hz, 3H), 1.19 (t, J = 7.06Hz, 3H), 0.90-0.87 (m, 6H); 31P NMR (DMS0-d6,162MHz) S (ppm) 8 · 17 (s, IP); MS (ESI) m / z = 567.5 (MH +).

[0417] 实施例3 [0417] Example 3

[0418] (化合物103) [0418] (Compound 103)

[0419] 4-氨基-I- [ (2R,3S,4S,5R) -5-[[(苯甲基氨基)-[(5-硝基-2-呋喃基)甲氧基]磷酰基]氧基甲基]-3,4-二羟基-四氢噻吩-2-基]嘧啶-2-酮 [0419] 4-amino--I- [(2R, 3S, 4S, 5R) -5 - [[(benzylamino) - [(5-nitro-2-furyl) methoxy] phosphoryl] oxymethyl] -3,4 - dihydroxy-tetrahydro-thiophen-2-yl] pyrimidin-2-one

[0420] [0420]

Figure CN108368147AD00552

[0421] 化合物103根据方案2和通用程序B,利用试剂B3来合成。 [0421] Compound 103 Scheme 2 and general procedure B, using reagent synthesized B3.

[0422] 化合物103 (非对映异构体1):固体;1H NMR(DMS0-d6,400MHz) δ (ppm) 7.86 (d,J = 7·53Ηζ,1Η),7.67(d,J = 3.77Hz,lH),7.34-7.29(m,4H),7·27-7·21 (m,lH),7.17(brs,lH), 7.08(brs,lH),6.89(d,J = 3.77Hz,lH),6.45(d,J = 4.90Hz,lH),5.85-5.76 (m,2H),5.69 (d,J = 7.53Hz,lH),5.57 (d,J = 3.86Hz,lH),5·04-4·93 (m,2H),4·37-4·31 (m,lH),4.08- 3.97 (m,5H) ;31P NMR (DMS0-d6,162MHz)S(ppm)9.94 (s,lP) ;MS(ESI)m/z = 554.4(MH+)。 [0422] Compound 103 (diastereomer 1): solid; 1H NMR (DMS0-d6,400MHz) δ (ppm) 7.86 (d, J = 7 · 53Ηζ, 1Η), 7.67 (d, J = 3.77 hz, lH), 7.34-7.29 (m, 4H), 7 · 27-7 · 21 (m, lH), 7.17 (brs, lH), 7.08 (brs, lH), 6.89 (d, J = 3.77Hz, lH), 6.45 (d, J = 4.90Hz, lH), 5.85-5.76 (m, 2H), 5.69 (d, J = 7.53Hz, lH), 5.57 (d, J = 3.86Hz, lH), 5 · 04-4 · 93 (m, 2H), 4 · 37-4 · 31 (m, lH), 4.08- 3.97 (m, 5H); 31P NMR (DMS0-d6,162MHz) S (ppm) 9.94 (s, lP); MS (ESI) m / z = 554.4 (MH +).

[0423] 化合物103 (非对映异构体2):固体;1H NMR(DMS0-d6,400MHz) δ (ppm) 7.88 (d,J = 7·50Ηζ,1Η),7.67(d,J = 3.59Hz,lH),7.32-7.29 (m,4H),7·27-7·21 (m,lH),7.17(brs,lH), 7.08(brs,lH),6.89(d,J = 3.75Hz,lH),6.45(d,J = 4.84Hz,lH),5.85-5.78 (m,lH),5.77 (d,J = 5.16Hz,lH),5.71 (d,J = 7.50Hz,lH),5.58(d,J = 3.97Hz,lH),5.04-4.94(m,2H), 4.38-4.27(m,lH),4.12-4.05(m,2H),4.02-3.97(m,3H),3.38-3.37 (m,lH);31PNMR(DMS0-d6,162MHz) δ (ppm) 9.93 (s,IP) ;MS (ESI) m/z = 554.4 (MH+)。 [0423] Compound 103 (diastereomer 2): solid; 1H NMR (DMS0-d6,400MHz) δ (ppm) 7.88 (d, J = 7 · 50Ηζ, 1Η), 7.67 (d, J = 3.59 hz, lH), 7.32-7.29 (m, 4H), 7 · 27-7 · 21 (m, lH), 7.17 (brs, lH), 7.08 (brs, lH), 6.89 (d, J = 3.75Hz, lH), 6.45 (d, J = 4.84Hz, lH), 5.85-5.78 (m, lH), 5.77 (d, J = 5.16Hz, lH), 5.71 (d, J = 7.50Hz, lH), 5.58 ( d, J = 3.97Hz, lH), 5.04-4.94 (m, 2H), 4.38-4.27 (m, lH), 4.12-4.05 (m, 2H), 4.02-3.97 (m, 3H), 3.38-3.37 ( m, lH); 31PNMR (DMS0-d6,162MHz) δ (ppm) 9.93 (s, IP); MS (ESI) m / z = 554.4 (MH +).

[0424] 实施例4 [0424] Example 4

[0425] (化合物104b) [0425] (Compound 104b)

[0426] (25)-2-[[[(2尺,35,45,5!0-5-(4-氨基-2-氧代基-嘧啶-1-基)-3,4-二羟基-四氢噻吩-2-基]甲氧基-(2-甲氧基-2-氧代基-乙氧基)磷酰基]氨基]-4-甲基-戊酸甲酯 [0426] (25) -2 - [[[(2 feet, 35,45,5 0-5- (4-amino-2-yl! - 1-yl) -3,4-dihydroxy - tetrahydro-thiophen-2-yl] methoxy - (2-methoxy-2-oxo-ethoxy) - phosphoryl] amino] -4-methyl - pentanoic acid methyl ester

[0427 [0427

Figure CN108368147AD00561

[0428] 化合物104b根据方案2和通用程序B,利用试剂M来合成。 [0428] compound 104b according to Scheme 2 and general procedure B, using reagent synthesized M.

[0429] 化合物104b (非对映异构体1):固体;1H NMR(DMS0-d6,400MHz) δ (ppm) 7.89 (d,J = 7·47Ηζ,1Η),7· 17 (brs,lH),7·08 (brs,lH),6·45 (d,J = 4.78Hz,lH),5·76 (d,J = 5.09Hz, 1H),5·71 (d,J = 7.47Hz,lH),5.69(dd,J=12.87Hz和10·28Ηζ,1Η),5.55(d,J = 4.00Hz, 1H),4·53-4.50 (m,2H),4·35-4.30 (m,lH),4· 10-4.04 (m,2H),4.00-3.97 (m,lH),3·78-3.71 (m,lH),3.70(s,3H),3.64(s,3H),1.76-1.67 (m,lH),1.54-1.39 (m,2H),0.89-0.86 (m,6H) ;31P NMR (DMS〇-d6,162MHz) δ (ppm) 8 · 26 (s,IP) ; MS (ESI) m/z = 539 · 2 (MH+)。 [0429] Compound 104b (diastereomer 1): solid; 1H NMR (DMS0-d6,400MHz) δ (ppm) 7.89 (d, J = 7 · 47Ηζ, 1Η), 7 · 17 (brs, lH ), 7 · 08 (brs, lH), 6 · 45 (d, J = 4.78Hz, lH), 5 · 76 (d, J = 5.09Hz, 1H), 5 · 71 (d, J = 7.47Hz, lH), 5.69 (dd, J = 12.87Hz and 10 · 28Ηζ, 1Η), 5.55 (d, J = 4.00Hz, 1H), 4 · 53-4.50 (m, 2H), 4 · 35-4.30 (m, lH), 4 · 10-4.04 (m, 2H), 4.00-3.97 (m, lH), 3 · 78-3.71 (m, lH), 3.70 (s, 3H), 3.64 (s, 3H), 1.76- 1.67 (m, lH), 1.54-1.39 (m, 2H), 0.89-0.86 (m, 6H); 31P NMR (DMS〇-d6,162MHz) δ (ppm) 8 · 26 (s, IP); MS ( ESI) m / z = 539 · 2 (MH +).

[0430] 化合物104b (非对映异构体2):固体;1H NMR(DMS0-d6,400MHz) δ (ppm) 7.90 (d,J = 7·46Ηζ,1Η),7.18(brs,lH),7.08(brs,lH),6.45(d,J = 4.98Hz,lH),5.76(d,J = 5.11Hz, 1H),5.72 (d,J = 7.46Hz,1H),5.72 (dd,J= 13.27Hz和10.09Hz,1H),5.57 (d,J = 4.01Hz, 1H),4.53-4.42(m,2H),4.36-4.30 (m,lH),4·17-4·11 (m,lH),4.08-4.05 (m,lH),4·01-3·98 (m,lH),3.75-3.68 (m,lH),3.69(s,3H),3.63(s,3H),1.75-1.65 (m,lH),1.54-1.38(m,2H), 0 · 88 (d,J = 6 · 36Hz,3H),0 · 87 (d,J = 6 · 36Hz,3H) ; 31P NMR (DMS〇-d6,162MHz) δ (ppm) 8 · 13 (s, IP) ;MS (ESI) m/z = 539.2 (MH+) 〇 [0430] Compound 104b (Diastereomer 2): solid; 1H NMR (DMS0-d6,400MHz) δ (ppm) 7.90 (d, J = 7 · 46Ηζ, 1Η), 7.18 (brs, lH), 7.08 (brs, lH), 6.45 (d, J = 4.98Hz, lH), 5.76 (d, J = 5.11Hz, 1H), 5.72 (d, J = 7.46Hz, 1H), 5.72 (dd, J = 13.27 Hz and 10.09Hz, 1H), 5.57 (d, J = 4.01Hz, 1H), 4.53-4.42 (m, 2H), 4.36-4.30 (m, lH), 4 · 17-4 · 11 (m, lH) , 4.08-4.05 (m, lH), 4 · 01-3 · 98 (m, lH), 3.75-3.68 (m, lH), 3.69 (s, 3H), 3.63 (s, 3H), 1.75-1.65 ( m, lH), 1.54-1.38 (m, 2H), 0 · 88 (d, J = 6 · 36Hz, 3H), 0 · 87 (d, J = 6 · 36Hz, 3H); 31P NMR (DMS〇- d6,162MHz) δ (ppm) 8 · 13 (s, IP); MS (ESI) m / z = 539.2 (MH +) square

[0431] 实施例5 [0431] Example 5

[0432] (化合物105) [0432] (Compound 105)

[0433] 4-氨基-l-[ (2R,3S,4S,5R) -5-[[(苯甲基氨基)-[2-(叔丁基二硫基)乙氧基]磷酰基]氧基甲基]-3,4-二羟基-四氢噻吩-2-基]嘧啶-2-酮 [0433] 4-amino--l- [(2R, 3S, 4S, 5R) -5 - [[(benzylamino) - [2- (tert-butylthio) ethoxy] phosphoryl] oxy yl methyl] -3,4 - dihydroxy-tetrahydro-thiophen-2-yl] pyrimidin-2-one

[0434] [0434]

Figure CN108368147AD00571

[0435] 化合物105根据方案2和通用程序B,利用试剂B5来合成。 [0435] Compound 105 Scheme 2 and general procedure B, using reagent synthesized B5.

[0436] 化合物105 (非对映异构体1):固体;1H NMR(DMS0-d6,400MHz) δ (ppm) 7.88 (d,J = 7·55Ηζ,1Η),7.36-7.30 (m,4H),7.27-7.22 (m,2H),7·11 (brs,lH),6.44(d,J = 4.86Hz,lH), 5.76 (d,J = 5.12Hz,lH),5.70 (d,J = 7.55Hz,lH),5·70-5·63 (m,lH),5.57 (d,J = 3.97Hz, 1H),4.34-4.28(m,lH),4.09-3.97 (m,7H),3.38-3.36 (m,lH),2.92(t,J = 6.58Hz,2H),1.30 (s,9H) ; 31P NMR (DMS〇-d6,162MHz) δ (ppm) 9.61 (s,IP) ; MS (ESI) m/z = 577.0 (MH+)。 [0436] Compound 105 (diastereomer 1): solid; 1H NMR (DMS0-d6,400MHz) δ (ppm) 7.88 (d, J = 7 · 55Ηζ, 1Η), 7.36-7.30 (m, 4H ), 7.27-7.22 (m, 2H), 7 · 11 (brs, lH), 6.44 (d, J = 4.86Hz, lH), 5.76 (d, J = 5.12Hz, lH), 5.70 (d, J = 7.55Hz, lH), 5 · 70-5 · 63 (m, lH), 5.57 (d, J = 3.97Hz, 1H), 4.34-4.28 (m, lH), 4.09-3.97 (m, 7H), 3.38 -3.36 (m, lH), 2.92 (t, J = 6.58Hz, 2H), 1.30 (s, 9H); 31P NMR (DMS〇-d6,162MHz) δ (ppm) 9.61 (s, IP); MS ( ESI) m / z = 577.0 (MH +).

[0437] 化合物105 (非对映异构体2):固体;1H NMR(DMS0-d6,400MHz) δ (ppm) 7.90 (d,J = 7·46Ηζ,1Η),7.35-7.30 (m,4H),7.28-7.22 (m,lH),7.18(brs,lH),7.08(brs,lH),6.45(d,J = 4·92Ηζ,1Η),5.76 (d,J = 5.16Hz,1H),5.71 (d,J = 7.46Hz,lH),5.70-5.63 (m,lH),5.57 (d,J = 4. OlHz,1H),4.30-4.24 (m,lH),4.11-3.96 (m,7H),3.38-3.36 (m,lH),2.92 (t,J = 6 · 64Hz,2H),I · 29 (s,9H) ; 31P NMR (DMS〇-d6,162MHz) δ (ppm) 9 · 57 (s,IP) ; MS (ESI) m/z = 577 · 0 (MH+) 〇 [0437] Compound 105 (diastereomer 2): solid; 1H NMR (DMS0-d6,400MHz) δ (ppm) 7.90 (d, J = 7 · 46Ηζ, 1Η), 7.35-7.30 (m, 4H ), 7.28-7.22 (m, lH), 7.18 (brs, lH), 7.08 (brs, lH), 6.45 (d, J = 4 · 92Ηζ, 1Η), 5.76 (d, J = 5.16Hz, 1H), 5.71 (d, J = 7.46Hz, lH), 5.70-5.63 (m, lH), 5.57 (d, J = 4. OlHz, 1H), 4.30-4.24 (m, lH), 4.11-3.96 (m, 7H ), 3.38-3.36 (m, lH), 2.92 (t, J = 6 · 64Hz, 2H), I · 29 (s, 9H); 31P NMR (DMS〇-d6,162MHz) δ (ppm) 9 · 57 (s, IP); MS (ESI) m / z = 577 · 0 (MH +) square

[0438] 实施例6 [0438] Example 6

[0439] (化合物106b) [0439] (Compound 106b)

[0440] 4-氨基-I- [ (2R,3S,4S,5R) -4-[(苯甲基氨基)-[(3-甲基-2-硝基-咪唑-4-基)甲氧基]磷酰基]氧基-3-羟基-5-(轻基甲基)四氢噻吩-2-基]嘧啶-2-酮 [0440] 4-amino--I- [(2R, 3S, 4S, 5R) -4 - [(benzylamino) - [(3-methyl-2-nitro - imidazol-4-yl) methoxy yl] phosphoryl] oxy-3-hydroxy-5- (light-ylmethyl) tetrahydro-thiophen-2-yl] pyrimidin-2-one

[0441] [0441]

Figure CN108368147AD00572

[0442] 化合物106b根据方案2和通用程序B,利用试剂B6来合成。 [0442] compound 106b according to Scheme 2 and general procedure B, using reagent synthesized B6.

[0443] 化合物10613:¾ NMR (DMS0-d6,400MHz) δ (ppm) 7.97 (d,J = 7.22Hz,lH),7·30-7·26 (m,3H),7.23-7.15(m,5H),6.45(d,J = 5.51Hz,lH),5.83(d,J = 4.86Hz,lH),5.77-5.70 (m, 2H),5.17(t,J = 5.51z,lH),4.94-4.87(m,2H),4.66-4.61(m,lH),4.28-4.24(m,lH),3.92-3.84 (m,2H),3.82-3.76 (m,lH),3.78 (s,3H) ,3.66-3.60 (m,lH) ,3.28-3.24 (m,2H) ;31P NMR (DMS0-d6,162MHz)S(ppm)9.35(s,lP) ;MS(ESI)m/z = 568.1 (MH+)。 [0443] Compound 10613: ¾ NMR (DMS0-d6,400MHz) δ (ppm) 7.97 (d, J = 7.22Hz, lH), 7 · 30-7 · 26 (m, 3H), 7.23-7.15 (m, 5H), 6.45 (d, J = 5.51Hz, lH), 5.83 (d, J = 4.86Hz, lH), 5.77-5.70 (m, 2H), 5.17 (t, J = 5.51z, lH), 4.94- 4.87 (m, 2H), 4.66-4.61 (m, lH), 4.28-4.24 (m, lH), 3.92-3.84 (m, 2H), 3.82-3.76 (m, lH), 3.78 (s, 3H), 3.66-3.60 (m, lH), 3.28-3.24 (m, 2H); 31P NMR (DMS0-d6,162MHz) S (ppm) 9.35 (s, lP); MS (ESI) m / z = 568.1 (MH +) .

[0444] 实施例6a [0444] Example 6a

[0445] 化合物106a根据方案2和通用程序B,利用试剂B6来合成。 [0445] compound 106a according to Scheme 2 and general procedure B, using reagent synthesized B6.

[0446] 制备化合物107和化合物C2 [0446] Preparation of compound 107 and compound C2

[0447] 化合物107根据方案2和以下通用程序C来合成。 [0447] Compound 107 was synthesized according to Scheme 2 and the following general procedure C.

[0448] 在(TC下向化合物A2 (3.38mmol)和2- (2,2-二甲基-3-三苯甲基氧基丙酰基)-硫基乙氧基次膦酸(5.08mmol)于卩比啶(12mL/mmol)中的溶液缓慢加入特戊酰氯(6.77mmol)。将反应混合物在0 °C下搅拌1小时并在室温下搅拌2小时。反应由LC/MS监测。反应混合物用IM NH4Cl溶液淬灭并用乙酸乙酯萃取。将有机层干燥,过滤并在减压下浓缩,得到所期望的中间体。 [0448] In (the TC of compound A2 (3.38mmol) and 2- (2,2-dimethyl-3-trityloxy propionyl) - thio-ethoxy-phosphinic acid (5.08 mmol) solution (12mL / mmol) in pyridine slowly than in Jie pivaloyl chloride (6.77 mmol). the reaction mixture was stirred for 1 hour at 0 ° C and stirred at room temperature for 2 hours the reaction by LC / MS. the reaction mixture was quenched with IM NH4Cl solution and extracted with ethyl acetate. the organic layer was dried, filtered and concentrated under reduced pressure to give the desired intermediate.

[0449] 在室温下向此中间体(I. Immol)于四氯化碳(20mL/mmol)和DCM (15mL/mmol)中的溶液加入苯甲胺(5.5mmol)和三乙胺(6.6mmol)。 [0449] To a solution of this intermediate (I. Immol) in carbon tetrachloride (20mL / mmol) and DCM (15mL / mmol) was added benzylamine at room temperature (5.5mmol) and triethylamine (6.6 mmol ). 将反应混合物搅拌过周末,并且接着在减压下浓缩并通过二氧化硅快速色谱法(DCM/甲醇)纯化,得到所期望的中间体。 The reaction mixture was stirred over the weekend, and then concentrated and purified by silica flash chromatography (DCM / methanol) under reduced pressure to give the desired intermediate.

[0450] 在氮气下向此中间体(0.49mmol)于DCM (30mL/mmol)中的溶液加入三氟乙酸(7.4mmol)。 [0450] To a solution of this intermediate (0.49 mmol) in DCM (30mL / mmol) was added under nitrogen trifluoroacetic acid (7.4mmol). 将反应混合物在室温下搅拌过夜并通过二氧化硅快速色谱法(DCM/甲醇:0至20 %),接着MS-制备型HPLC纯化,得到所期望的非对映异构体混合物C2。 The reaction mixture was stirred overnight at room temperature and purified by silica flash chromatography: followed by purification (DCM / methanol 0 to 20%) MS- preparative HPLC, to give the desired diastereomeric mixture C2.

[0451] 使化合物C2 (0.35mmol)溶于7N氨的甲醇溶液(50mL/mmol)中且将反应混合物在室温下搅拌4小时。 [0451] Compound C2 (0.35mmol) was dissolved in 7N ammonia in methanol (50mL / mmol) and the reaction mixture was stirred at room temperature for 4 hours. 反应混合物在减压下浓缩并通过RP-18色谱法(H2(VCH3CN),接着RP-18色谱法(H20+TEAB/CH3CN)纯化,得到呈固体状的所期望的化合物。 The reaction mixture was concentrated and followed by chromatography on RP-18 (H20 + TEAB / CH3CN) and purified by RP-18 chromatography (H2 (VCH3CN), as a solid to give the desired compound under reduced pressure.

[0452] 化合物C2:3-羟基-2,2-二甲基-丙硫醇S- [2- [ [ (2R,3S,4S,5R) -5- (4-氨基-2-氧代基-嘧啶-1-基)-3,4_二羟基-四氢噻吩-2-基]甲氧基-(苯甲基氨基)磷酰基]氧基乙基] 酯: [0452] Compound C2: 3- hydroxy-2,2-dimethyl - propanethiol S- [2- [[(2R, 3S, 4S, 5R) -5- (4- amino-2-yl - pyrimidin-1-yl) -3,4_ - dihydroxy-tetrahydro-thiophen-2-yl] methoxy - (phenylmethyl amino) phosphoryl] oxy ethyl] ester:

[0453] 31P NMR(DMS0-d6,162MHz) δ (ppm) 9.51 (s,0.5P) , 9.48 (s, 0.5P) ;MS(ESI)m/z = 589 · 0 (MH+) 〇 [0453] 31P NMR (DMS0-d6,162MHz) δ (ppm) 9.51 (s, 0.5P), 9.48 (s, 0.5P); MS (ESI) m / z = 589 · 0 (MH +) square

[0454] 实施例7 [0454] Example 7

[0455] (化合物107) [0455] (Compound 107)

[0456] [ (2R,3S,4S,5R) -5- (4-氨基-2-氧代基-嘧啶-I-基)-3,4-二羟基-四氢噻吩-2-基]甲氧基-N-苯甲基-氨基磷酸 [0456] [(2R, 3S, 4S, 5R) -5- (4- amino-2-yl - -I- pyrimidin-yl) -3,4 - dihydroxy-tetrahydro-thiophen-2-yl] methyl -N- benzyl group - amino acid

[0457] [0457]

Figure CN108368147AD00581

[0458] 化合物107:咕匪1?(0150-(16,4001!^)5(??111)7.93((1,了= 7.50!^,1!1),7.35-7.33 (m,2H),7.29-7.25 (m,2H),7.19-7.15(m,2H),7.04(brs,lH),6.37(d,J = 5.27Hz,lH),6.24 (brs,lH),5.92(brs,lH),5·71 (d,J = 7.49Hz,lH),4.26(t,J = 4.21Hz,lH),4.07-4.00 (m, 1H),3.95 (t,J = 5.05Hz,lH),3.90 (d,J = 9.38Hz,2H),3.75-3.68 (m,lH),3.27-3.23 (m, 1H) ;31P NMR(DMS0-d6,162MHz)S(ppm)6.72(s,lP) ;MS(ESI)m/z = 429.0(MH+)。 [0458] Compound 107: 1 bandit cushions (0150- (16,4001 ^) 5 (111 ??) 7.93 ((1, a = 7.50 ^, 1 1), 7.35-7.33 (m, 2H)?!!! , 7.29-7.25 (m, 2H), 7.19-7.15 (m, 2H), 7.04 (brs, lH), 6.37 (d, J = 5.27Hz, lH), 6.24 (brs, lH), 5.92 (brs, lH ), 5 · 71 (d, J = 7.49Hz, lH), 4.26 (t, J = 4.21Hz, lH), 4.07-4.00 (m, 1H), 3.95 (t, J = 5.05Hz, lH), 3.90 (d, J = 9.38Hz, 2H), 3.75-3.68 (m, lH), 3.27-3.23 (m, 1H); 31P NMR (DMS0-d6,162MHz) S (ppm) 6.72 (s, lP); MS (ESI) m / z = 429.0 (MH +).

[0459] 实施例7a [0459] Example 7a

[0460] (化合物C2) [0460] (compound C2)

[0461 ] 3-羟基-2,2-二甲基-丙硫醇S- [2- [ [ (2R,3S,4S,5R) -5- (4-氨基-2-氧代基-嘧啶-1-基)-3,4_二羟基-四氢噻吩-2-基]甲氧基_(苯甲基氨基)磷酰基]氧基乙基]酯 [0461] 3-hydroxy-2,2-dimethyl - propanethiol S- [2- [[(2R, 3S, 4S, 5R) -5- (4- amino-2-oxo - pyrimidine - 1- yl) -3,4_ - dihydroxy-tetrahydro-thiophen-2-yl] methoxy _ (phenylmethyl amino) phosphoryl] oxy ethyl] ester

[0462] 化合物C2:31P 匪R (DMSO-Cl6,162MHz) δ (ppm) 9.51 (s,0.5P),9.48 (s,0.5P) ;MS (ESI)m/z = 589.0 (MH+)。 [0462] Compound C2: 31P bandit R (DMSO-Cl6,162MHz) δ (ppm) 9.51 (s, 0.5P), 9.48 (s, 0.5P); MS (ESI) m / z = 589.0 (MH +).

[0463] 方案4:制备化合物108b [0463] Scheme 4: Preparation of Compound 108b

[046^ [046 ^

Figure CN108368147AD00591

[0465] 实施例8 [0465] Example 8

[0466] (化合物108b) [0466] (Compound 108b)

[0467] 乙酸[(2S) -2_[[ (4aR,6R,7S,7aS) -6- (4-氨基-2-氧代基-嘧啶-1-基)-7-羟基-2-氧代基-4a,6,7,7a-四氢-4H-噻吩并[3,2-d] [1,3,2]二氧杂膦酰-2-基]氨基]丙基]酯 [0467] acetic acid [(2S) -2 _ [[(4aR, 6R, 7S, 7aS) -6- (4- amino-2-oxo - 1-yl) -7-hydroxy-2-oxo group -4a, 6,7,7a- tetrahydro -4H- thieno [3,2-d] [1,3,2] dioxa-phosphono-2-yl] amino] propyl] ester

[0468] [0468]

Figure CN108368147AD00592

[0469] 向化合物A2 (1.32mmol)于DCM(25mL/mmol)中的悬浮液逐滴加入化合物D2 (1.59mmol)于THF (lOmL/mmol)中的溶液并接着加入1,8-二氮杂双环[5.4.0] ^-7-烯(3.12mmol)于乙腈(25mL/mmol)中的溶液。 In [0469] to compound A2 (1.32mmol) in DCM (25mL / mmol) was added dropwise to a suspension of compound D2 (1.59mmol) in THF (lOmL / mmol) was added and then 1,8- (25mL / mmol) was bicyclo [5.4.0] ^ 7-ene (3.12 mmol) in acetonitrile. 将反应混合物在室温下在氮气下搅拌1天。 The reaction mixture was stirred for 1 day at room temperature under nitrogen. 将反应混合物用DCM稀释并用饱和NaHCO3水溶液洗涤5次。 The reaction mixture was diluted with DCM and washed five times with saturated aqueous NaHCO3. 水层用DCM再萃取一次。 The aqueous layer was re-extracted once with DCM. 将合并的有机层干燥,过滤并在减压下浓缩。 The combined organic layers were dried, filtered and concentrated under reduced pressure. 粗残余物通过硅胶快速色谱法(DCM/MeOH)纯化,得到呈固体状的所期望的中间体化合物。 The crude residue was purified by flash chromatography on silica gel (DCM / MeOH) to give as a solid of the desired intermediate compound. 在氮气下此化合物溶于无水DCM(lOmL/mmol)中并加入三氟乙酸(0.8mL/mm〇l)。 This compound was dissolved under nitrogen in anhydrous DCM (lOmL / mmol) and trifluoroacetic acid (0.8mL / mm〇l). 将反应混合物在室温下搅拌3小时,接着混合物浓缩至1/3溶剂体积并负载至PE-AX滤筒以清除TFA。 The reaction mixture was stirred at room temperature for 3 hours and then the mixture was concentrated to 1/3 volume of the solvent loaded onto a PE-AX and cartridge to remove TFA. 将目标化合物用乙腈洗提并在减压下浓缩。 The title compound eluted with acetonitrile and concentrated under reduced pressure. 粗残余物通过二氧化硅快速色谱法(DCM/MeOH)纯化两次,得到呈固体状的呈单一非对映异构体形式的所期望的化合物。 The crude residue was purified by flash chromatography on silica (DCM / MeOH) purified twice to give the desired as a single non-enantiomeric form of the compounds in solid form.

[0470] 化合物108b (1 种非对映异构体):¾ NMR (DMSO-Cl6,400MHz) δ (ppm) 7.85 (d,J = 7·39Ηζ,1Η),7·23 (brs,lH),7· 15 (brs,lH),6·42 (d,J = 8.35Hz,lH),6·03 (d,J = 5.64Hz, 1Η),5· 77 (d,J = 7 ·39Ηζ,1Η),5· 55 (dd,J= 13.53Hz和10.03Hz,1Η),4.57-4.52 (m,lH), 4.47-4.36 (m,2H),4·33-4·27 (m,lH),3·88-3·80 (m,2H),3·47-3·40 (m,lH),2·00 (s,3H), 1.06 (d,J = 6.58Hz,3H) ;31P NMR(DMS0-d6,162MHz) δ (ppm) 5.39 (s,lP) ;MS(ESI)m/z = 421.0 (MH+) 〇 [0470] Compound 108b (1 Species diastereomer thereof): ¾ NMR (DMSO-Cl6,400MHz) δ (ppm) 7.85 (d, J = 7 · 39Ηζ, 1Η), 7 · 23 (brs, lH) , 7 · 15 (brs, lH), 6 · 42 (d, J = 8.35Hz, lH), 6 · 03 (d, J = 5.64Hz, 1Η), 5 · 77 (d, J = 7 · 39Ηζ, 1Η), 5 · 55 (dd, J = 13.53Hz and 10.03Hz, 1Η), 4.57-4.52 (m, lH), 4.47-4.36 (m, 2H), 4 · 33-4 · 27 (m, lH) , 3 · 88-3 · 80 (m, 2H), 3 · 47-3 · 40 (m, lH), 2 · 00 (s, 3H), 1.06 (d, J = 6.58Hz, 3H); 31P NMR (DMS0-d6,162MHz) δ (ppm) 5.39 (s, lP); MS (ESI) m / z = 421.0 (MH +) square

[0471] 实施例9 [0471] Example 9

[0472] 体外抑制 [0472] In vitro inhibition of

[0473] 材料 [0473] Materials

[0474] 使以下细胞系的细胞在补充有L-谷氨酰胺和10%FBS的RPMI-1640中生长: [0474] Cells following cell lines L- glutamine and supplemented with 10% FBS, grown in RPMI-1640:

[0475] CCRF-CEM; CCRF-CEM-耐阿糖胞苷性;HL-60; K56 2; CFPAC-1; Mi aPACA-2; BxPC-3; PANC-I; !fepG2;MDA-MB-231;HCT-116;A498;和NCI-H69 [0475] CCRF-CEM; CCRF-CEM- corrosion resistance cytarabine; HL-60; K56 2; CFPAC-1; Mi aPACA-2; BxPC-3; PANC-I;! FepG2; MDA-MB-231 ; HCT-116; A498; and NCI-H69

[0476] 越 [0476] more

[0477] 每个细胞系用每孔最佳数目的细胞接种18个96孔平板,每孔的总体积是50yL。 [0477] Each cell line optimal number of cells per well were seeded in 96-well plates 18, total volume per well is 50yL. 平板静置过夜。 Left to stand overnight. 对于培养基对照物,将平板孔用IOOyL培养基接种。 For the control medium, the medium was inoculated plates IOOyL holes. 第二天,如下所述,细胞暴露于测试化合物。 The next day, as described below, cells were exposed to test compound. 与药物暴露同时,在第十八个平板上进行CTG测定,以进行0小时计数。 Drug exposure performed while CTG measured on an eighteenth plate counts for 0 hours.

[0478] 将化合物加入已经在平板上的细胞和培养基中,得到所需最终浓度。 [0478] The compound has been added to the culture medium and the cells on the plate, to give the desired final concentration. 将50yL培养基加入细胞对照孔,并将50yL混合物加入媒介物对照孔。 The cell medium was added to control wells 50yL, and the mixture was added 50yL vehicle control wells. 将ΙΟμΜ多柔比星加入适当孔中。 The ΙΟμΜ Doxorubicin was added to appropriate wells. 将暴露于测试化合物的细胞在37°C下孵育72小时,接着进行CTG测定。 The exposure to the test compound cells were incubated for 72 hours at 37 ° C, followed by measurement CTG.

[0479] CellTiter-Glo(CTG) [0479] CellTiter-Glo (CTG)

[0480] 在72小时暴露期结束时,将平板从37°C、5%C02孵育箱中移出以供CellTiter-Glo (CTG)测定并放在工作台上于室温下30分钟。 [0480] at 72 hour exposure period ends, the plates were removed from the 37 ° C, 5% C02 incubator for CellTiter-Glo (CTG) and measured on a work bench at room temperature for 30 minutes. 加入IOOyL CellTiter-Glo试剂并混合2分钟, 接着在室温下进一步孵育10分钟。 IOOyL CellTiter-Glo Reagent was added and mixed for 2 minutes, followed by further incubation at room temperature for 10 minutes. 使用Synergy 4.0记录发光。 Synergy 4.0 using recording light.

[0481] 所有的例示化合物都根据此方法进行测试并且发现其在每个细胞系的IC5q值都小于ΙΟΟμΜ。 All exemplified compound [0481] According to this method were tested and found to be less than the value IC5q ΙΟΟμΜ in each cell line. 化合物的结果提供于表1和表2中。 Results for compounds are provided in Table 1 and Table 2.

[0482] 表1-CCRF-CEM、CCRF-CEM-耐阿糖胞苷性、HL-60、K562、CFPAC-l、MiaPACA-2 和BxPC-3的体外抑制 In vitro [0482] Table 1-CCRF-CEM, CCRF-CEM- corrosion resistance cytarabine, HL-60, K562, CFPAC-l, MiaPACA-2, and BxPC-3 inhibition

[0483] [0483]

Figure CN108368147AD00601

Figure CN108368147AD00611

I I

Figure CN108368147AD00621

[0486]表2-?厶从>1、临口62、1\0^-1\^-231、!1(:1'-116^498和从:1-册9的体外抑制 [0486] From Table 2 - Si> 1, 62,1 Pro port \ 0 -1 \ ^ --1 (231:? ^ 1'-116 and from 498: 1- inhibits volumes 9!

Figure CN108368147AD00622

Figure CN108368147AD00631

[0489] 表1和2中的IC5q值如下: [0489] Table IC5q values ​​1 and 2 as follows:

[0490] Α=<1μΜ [0490] Α = <1μΜ

Figure CN108368147AD00632

[0491] [0491]

[0492] [0492]

[0493] 当平板孵育48小时时化合物对AML样品的离体作用示于表3中: [0493] When the compound of the plates incubated for 48 hours in vitro effect of AML samples shown in Table 3:

Figure CN108368147AD00633

Figure CN108368147AD00641

Figure CN108368147AD00651

[( [(

Figure CN108368147AD00661

[0498] EC5q值提供如下: [0498] EC5q value is provided as follows:

[0499] [0499]

Figure CN108368147AD00662

[0500] Emax值提供如下: [0500] Emax values ​​provided as follows:

[0501] A = 0-10%;B = 10-20%;C>20%。 [0501] A = 0-10%; B = 10-20%; C> 20%.

Claims (13)

  1. I. 一种根据式I的化合物: I. The compound of formula I is:
    Figure CN108368147AC00021
    或其药学上可接受的盐,其中: R1与R2中的一个是氢并且另一个是 Or a pharmaceutically acceptable salt thereof, wherein: R1 and R2 is a hydrogen and the other is
    Figure CN108368147AC00022
    或R1和R2连同其连接的两个氧原子一起形成以下环结构: Or R1 and R2 together with the two oxygen atoms connected to form the following ring structure:
    Figure CN108368147AC00023
    R3是氢、C1-K)烷基、C2-n烯基、C2-n炔基、C1-H)烷氧基羰基C1-K)烷基、C1-K)烷基羰基硫基C1-K)烷基、C1-K)烷基二硫基Ck烷基、芳基或杂芳基C1-K)烷基,其中烷基任选地经一个、两个或三个独立地选自卤素和羟基的取代基取代,并且杂芳基经一个或两个选自Cho烷基和硝基的取代基取代; R4是氢或C1-K)烷基; R5是Cl-IQ烧氧基幾基、C3-1Q环烧氧基幾基、Cl-IQ烧基幾氧基Cl-IQ烧基、C3-1Q环烧基幾氧基、芳基、芳氧基、C1-K)烷基芳基、芳基C1-K)烷基、芳基C1-K)烷氧基羰基、芳氧基羰基、杂芳基、 杂芳基C1-K)烷基或C1-K)烷基杂芳基; R6是 R3 is hydrogen, C1-K) alkyl, C2-n alkenyl, C2-n alkynyl, C1-H) alkoxycarbonyl C1-K) alkyl, C1-K) alkylcarbonyl group C1-K ) alkyl, C1-K) alkyl disulfide Ck alkyl, aryl, or heteroaryl C1-K) alkyl, wherein alkyl is optionally substituted with one, two or three substituents independently selected from halogen and hydroxy substituents, aryl and heteroaryl groups substituted with one or two substituents selected from alkyl and nitro Cho substituents; R4 is hydrogen or C1-K) alkyl; R5 is Cl-IQ group burning several groups, C3-1Q cycloalkyl group burning several groups, Cl-IQ group burn burn Cl-IQ several yloxy group, C3-1Q cycloalkyl group fired several group, aryl group, aryloxy group, C1-K) alkyl aryl, aryl-C1-K) alkyl, aryl C1-K) alkoxycarbonyl group, an aryloxycarbonyl group, a heteroaryl group, heteroaryl C1-K) alkyl, or C1-K) alkyl heteroaryl; R6 Yes
    Figure CN108368147AC00024
    或-OR3;并且W是0或S, 条件是不包括下式化合物: Or -OR3; and W is 0 or S, with the proviso that a compound of the formula:
    Figure CN108368147AC00031
    其中R3'是芳基或任选取代的杂芳基,R4'是(^-1()烧基,烧基、C3-K)环烷基、芳基C1-K)烷基或芳基,并且W是O。 Wherein R3 'is aryl or optionally substituted heteroaryl, R4' is (-1 () group to burn, burn group, C3-K) cycloalkyl, aryl C1-K) alkyl or aryl, and W is O.
  2. 2. 如权利要求1所述的化合物,其中R1与R2中的一个是氢并且另一个是 2. The compound according to claim 1, wherein one of R1 and R2 is hydrogen and the other is
    Figure CN108368147AC00032
    或其药学上可接受的盐。 Or a pharmaceutically acceptable salt thereof.
  3. 3. 如权利要求1所述的化合物,其中R1和R2连同其连接的两个氧原子一起形成以下环结构: 3. The compound according to claim 1, wherein R1 and R2 together with the two oxygen atoms connected to form the following ring structure:
    Figure CN108368147AC00033
    或其药学上可接受的盐。 Or a pharmaceutically acceptable salt thereof.
  4. 4. 如权利要求1所述的化合物,其具有式II: 4. The compound according to claim 1, having the formula II:
    Figure CN108368147AC00034
    或其药学上可接受的盐, 条件是不包括下式化合物: Or a pharmaceutically acceptable salt thereof, with the proviso that a compound of the formula:
    Figure CN108368147AC00041
    其中R3是芳基或任选取代的杂芳基,妒是&amp;-1()烷基,1^是&amp;-6烷基、C3-1Q环烷基、芳基&amp;-10 烷基或芳基,并且W是〇或S。 Wherein R3 is an optionally substituted aryl or heteroaryl, is jealous & amp; -1 () alkyl, 1 ^ a & amp; -6 alkyl, C3-1Q cycloalkyl, aryl, & amp; -10 alkyl or an aryl group, and W is a square or S.
  5. 5. 如权利要求1所述的化合物,其具有式IV: 5. The compound according to claim 1, having formula IV:
    Figure CN108368147AC00042
    或其药学上可接受的盐。 Or a pharmaceutically acceptable salt thereof.
  6. 6. 如任一前述权利要求所述的化合物,其中W是0。 6. A compound according to any preceding claim, wherein W is 0.
  7. 7. —种化合物,其选自以下各物: 7. - compounds selected from the following composition:
    Figure CN108368147AC00043
    Figure CN108368147AC00051
    和其药学上可接受的盐。 And pharmaceutically acceptable salts thereof.
  8. 8. —种药物组合物,其包含如任一前述权利要求所述的化合物或药学上可接受的盐以及药学上可接受的载体或稀释剂。 8. - pharmaceutical compositions, comprising any pharmaceutically acceptable one of the preceding claims or a pharmaceutically acceptable salt of the compound and a pharmaceutically acceptable carrier or diluent.
  9. 9. 如权利要求1至7中任一项所述的化合物或其药用盐,其用于治疗中。 9. A compound according to any one of claims 7 or a pharmaceutically acceptable salt thereof as claimed in claim, for use in therapy.
  10. 10. 如权利要求1至7中任一项所述的化合物或其药用盐,其用于治疗或预防癌症。 10. A compound according to any one of claims 7 or a pharmaceutically acceptable salt thereof as claimed in claim, for the treatment or prevention of cancer.
  11. 11. 一种用于治疗癌症的方法,其包括施用有效治疗量的如权利要求1至7中任一项所述的化合物或其药学上可接受的盐或如权利要求8所述的组合物。 11. A method for treating cancer, which comprises administering a therapeutically effective amount of a compound of claim any one of or a pharmaceutically acceptable salt of any of 1 to 7 or a composition as claimed in claim 8 .
  12. 12. 如权利要求7所述的方法,其中所述化合物或组合物与一种或多种其它治疗剂组合施用。 12. The method according to claim 7, wherein said compound or composition with one or more other therapeutic agents administered in combination.
  13. 13. —种组合,其包含如权利要求1至7中任一项所述的化合物或其药学上可接受的盐和一种、两种、三种或更多种其它治疗剂。 13. - combination, comprising 1 to 7 Pharmaceutically The compound or a pharmaceutically acceptable salt thereof and one, two, three or more other therapeutic agents as claimed in claim.
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